7th Annual Conference September 24-27, 2018 ICBS 2018 Vancouver, Canada
Scientific Program
Towards Translational Impact
www.chemical-biology.org 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Acknowledgements
Towards Translational Impact September 24th – 27th, 2018 | Vancouver, BC
Local Program and Organizing Committee Tom Pfeifer, Centre for Drug Research and Development Roger Linington, Simon Fraser University Michel Roberge, University of British Columbia Nicolette Honson, Centre for Drug Research and Development
ICBS Organizing Committee Haian Fu, Chair, Emory University, USA Lixin Zhang, ECUST, China Sally-Ann Poulsen, Griffith University, Australia Jonathan Baell, Monash University, Australia Mahabir Gupta, University of Panama, Panama Junying Yuan, Harvard Medical School, USA Masatoshi Hagiwara, Kyoto University, Japan Petr Bartunek, CZ-OPENSCREEN and Institute of Molecular Jason Micklefield,The University of Manchester, UK Genetics, Czech Republic Siddhartha Roy, Bose Institute, India
ICBS Young Chemical Biologist Award 2018 Selection Committee Yimon Aye, Cornell University, USA Christian Ottmann, Technische Universiteit Eindhoven, Ratmir Derda, University of Alberta, Canada Netherlands Evripidis Gavathiotis, Albert Einstein College of Medicine, USA William Pomerantz, University of Minnesota, USA Kenjiro Hanaoka, University of Tokyo, Japan Qi Zhang, Fudan University, China
Recording of sessions (oral or poster) by audio, video, or still photography is strictly prohibited except with the advance permission of the author(s) and the conference organizers. Material contained in abstracts and presentations should be treated as personal communication and cited as such only with consent of the author(s).
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Table of Contents Acknowledgements...... 2 Thank you to our conference sponsors...... 16 ICBS Board of Directors...... 4 Keynote Speakers...... 17 About ICBS...... 4 Presentations...... 19 ICBS International Advisory Board...... 5 Rising Stars...... 48 Program at a Glance...... 6 Exhibitors...... 52 Welcome Letter...... 9 Poster Presenters...... 53 Program...... 10 Venue Map...... 55
Author Index
A H M T Masahiko Ajiro...... 32 Fred Haeckl...... 53 Dawei Ma...... 39 Mirelle Takaki...... 54 Rima Al-awar...... 31 Stephen J. Haggarty...... 36 Florian Mayerthaler...... 34 Lily Takeuchi...... 54 Matthew Alteen...... 54 Ting Han...... 19 Guillaume Médard...... 54 Hong Yee Tan...... 53 Sebastian Andrei...... 54 Evan Haney...... 54 James Meinig...... 53 Masayasu Toyomoto...... 54 Albert A. Antolin...... 25 Kenjiro Hanaoka...... 54 Poncho Meisenheimer...... 46 Michihiko Tsushima...... 53 Heather Arnaiz...... 53 Jason Hedges...... 54 Jason Micklefield...... 33 Doug Auld...... 54 Stephanie Heinzlmeir...... 54 Cameron Murray...... 54 V Nicole Houszka...... 53 David Vocadlo...... 21 B N I Anne Bang...... 37 Seyed Nasseri...... 53 W Jeremy M. Baskin...... 29 Takayuki Ikeno...... 53 Ali Nejatie...... 53 J.B. Brown...... 24 Alena Istrate...... 53 Sherry L Niessen...... 42 Chu Wang...... 49 Andrey Ivanov...... 25 Shaomeng Wang...... 19 Amy Weeks...... 54 C P Julian Wilke...... 53 J Robert Campbell...... 45 Andrew J. Phillips...... 43 Michael Winzker...... 53 Michelle Chang ...... 33 Namrata Jain...... 40 Sally-Ann Poulsen...... 27 Scott Wolkenberg...... 30 Wansang Cho...... 53 Francois Jean...... 54 Polina Prokofeva...... 54 Jeffrey Y.K. Wong...... 53 Michael Cohen...... 49 Shireen Jozi...... 54 Christina Woo...... 48 Q D K Y Kun Qian...... 54 Phillip Danby...... 54 Akane Kawamura...... 54 Kenzo Yamatsugu...... 53 Jennifer Kohler ...... 21 R Milka Kostic...... 27 E Casey Krusemark...... 31 Elena Reckzeh...... 53 Z Joseph Egan...... 53 Karson Kump...... 53 Anna Rutkowska-Klute...... 54 Charlotte Zammit...... 53 Syusuke Egoshi...... 53 Katherine Ryan...... 34 Cristina Zamora...... 22 L Andrew Zhang...... 42 F S Jin Zhang...... 45 Nicole LeGrow...... 53 Y. George Zheng...... 43 Victor Fadipe...... 54 Jasmine Li-Brubacher...... 53 Koichi Sasaki...... 54 Eric S. Fischer...... 20 Dennis Liu...... 53 Shinichi Sato...... 40 Frederic Friscourt...... 22 Scott Lovell...... 28 Saiko Shibata...... 53 David Lupton...... 39 Eline Sijbesma...... 54 Ellen M. Sletten...... 46 G Kimberly Snyder...... 38 Thota Ganesh...... 54 Mathieu Soetens...... 53 Thomas Garner...... 53 Barbara Sohr...... 53 Chloe Gerak...... 53 Paul Guyett...... 37 www.chemical-biology.org 3 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
ICBS Board of Directors
Lixin Zhang Haian Fu Jonathan Baell President (China) Chair of Board (USA) President Elect (Aus)
Rathnam Chaguturu Tom Pfeifer Masatoshi Hagiwara Treasurer (USA) Secretary (Can) (Japan)
Zaneta Nikolovska-Coleska Siddhartha Roy (USA) (India)
About ICBS The International Chemical Biology Society (ICBS) is an independent, nonprofit organization dedicated to promoting research and educational opportunities at the interface of chemistry and biology. ICBS provides an important international forum that brings together cross-disciplinary scientists from academia, non profit organizations, government, and industry to communicate new research and help translate the power of chemical biology to advance human health.
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ICBS International Advisory Board
Stephen Benkovic Sir Philip Cohen Jian Ding Penn State University of Dundee Shanghai Institute of Materia Medica
Chris Lipinski Ferid Murad Bernard Munos Melior Discovery George Washington University InnoThink
Litao Zhang Stuart Schreiber Paul Workman Bristol-Myers Squibb Harvard ICR-London
Tetsuo Nagano Leonard Zon Herbert Waldmann University of Tokyo HHM/Harvard Max Planck Institute of Molecular Physiology
Junying Yuan Harvard www.chemical-biology.org 5 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Program at a Glance
PRECONFERENCE: MONDAY, SEPTEMBER 24, 2018
8:00AM – 6:00PM Meeting Registration Playhouse Lobby
8:30AM – 9:00AM Coffee Playhouse Lobby
9:00AM – 5:00PM Young Chemical Biologists’ Forum Orchestra Right & Left
9:00AM – 9:10AM Welcome Orchestra Right & Left
Expert-Led Forum
9:10AM – 9:40AM Chemistry for Biologists Jonathan Baell, Monash University, Australia Assay Development and Screening Doug Auld, Novartis Institute for 9:10AM – 11:10AM 9:40AM – 10:10AM Biomedical Research, USA 10:10AM – 10:40AM Structural Biology Scott Lovell, University of Kansas, USA
10:40AM – 11:10AM Insights for Chemical Biology in Industry Andrew Zhang, AstraZeneca, USA
11:10AM – 11:25AM Coffee Break Playhouse Lobby
11:25AM – 12:45PM Student-Led Forum, Presenters 1 through 5 Orchestra Right & Left
12:45 PM – 1:45PM Lunch on Your Own
1:45PM – 3:00PM Student-Led Forum, Presenters 6 through 10 Orchestra Right & Left
Tech Talks Orchestra Right & Left
Creating and Deploying Next Generation Informatics Solutions – What 3:00PM – 3:30PM 3:00PM – 3:15PM We’ve Learned Along the Way Whitney Smith, Collaborative Drug Discovery, USA
3:15PM – 3:30PM Antibody-Drug Conjugates Graham Garnett, Zymeworks, Canada
3:30PM – 3:50PM Coffee Break and Exhibitor Viewing Salon A
3:50PM – 4:00 PM ICBS Conference Welcome Orchestra Right & Left
4:00PM – 4:05PM Keynote Introduction Orchestra Right & Left
Keynote – Craig M. Crews, Yale University, USA 4:05PM – 4:50PM PROTAC-mediated Protein Degradation: Making Problem Orchestra Right & Left Proteins Go Away ICBS Opening Reception and Young Chemical Biologists’ Social – Shark Club, Library Room 5:00PM – 8:00PM Off-Site | Shark Club Please join us for hors d’oeuvres and to network with your colleagues. CASH BAR is available
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CONFERENCE DAY 1: TUESDAY, SEPTEMBER 25, 2018
8:00AM – 5:00PM Meeting Registration Playhouse Lobby
8:30AM – 9:00AM Coffee Playhouse Lobby
9:00AM – 9:15AM Welcome Orchestra Right & Left Session I - Degradomics 9:15AM – 10:30PM Orchestra Right & Left Chair: Shaomeng Wang
10:30AM – 10:50AM Coffee Break and Exhibitor Viewing Salon A Session II – Glyco Chemical Biology 10:50AM – 12:10PM Orchestra Right & Left Chair: David Vocadlo
12:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing Salon A Open Panel Discussion Chair: Rathnam Chaguturu, iDDPartners, USA 1:15PM – 1:55PM Orchestra Right & Left Academic/Industry Partnerships to Promote Drug Discovery Through Chemical Biology
1:55PM – 2:10PM Conference Updates Orchestra Right & Left Session III – Computational Chemical Biology 2:10PM – 3:15PM Orchestra Right & Left Chair: J.B. Brown
3:15PM – 3:35PM Coffee Break and Exhibitor Viewing Salon A Session IV - Emerging and Other Topics 3:35PM – 4:55PM Orchestra Right & Left Chair: Sally-Ann Poulsen Poster Session on Balcony Level: Odd Numbered Presentations 5:00PM – 7:00PM Please join us for hors d’oeuvres and to network with your colleagues. Balcony Level CASH BAR is available.
CONFERENCE DAY 2: WEDNESDAY, SEPTEMBER 26, 2018
8:00AM – 5:00PM Meeting Registration Playhouse Lobby
8:30AM – 9:00AM Coffee Playhouse Lobby
9:00AM – 9:05AM Conference Updates Orchestra Right & Left Session V – The Chemical Biology – Medicinal Chemistry 9:05AM – 10:25AM Continuum Orchestra Right & Left Chair: Yves Auberson
10:25AM – 10:45AM Coffee Break and Exhibitor Viewing Salon A Session VI– Synthetic Biology 10:45AM – 12:15PM Orchestra Right & Left Chair: Jason Micklefield 12:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing Session VII – iPSC Chemical Biology 1:15PM – 2:35PM Orchestra Right & Left Chair: Steve Haggarty
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CONFERENCE DAY 2: WEDNESDAY, SEPTEMBER 26, 2018
2:35PM – 3:10 PM ICBS Business Meeting Orchestra Right & Left
3:10PM – 3:40PM Coffee Break and Exhibitor Viewing Salon A Rising Stars 3:40PM – 5:00PM Orchestra Right & Left Chair: Haian Fu Poster Session on Balcony Level: Even Numbered Presentations 5:00PM – 7:00PM Please join us for hors d’oeuvres and to network with your colleagues. Balcony Level CASH BAR is Available
CONFERENCE DAY 3: THURSDAY, SEPTEMBER 27, 2018
8:00AM – 4:00PM Meeting Registration Playhouse Lobby
8:30AM – 9:00AM Coffee Playhouse Lobby
9:00AM – 09:05AM Conference Updates Orchestra Right & Left
Session VIII – Synthetic Chemistry 9:05AM – 10:25AM Orchestra Right & Left Chair: David Lupton
10:25AM – 10:45AM Coffee Break and Exhibitor Viewing Salon A
10:45AM – 10:50AM Keynote Introduction Orchestra Right & Left
Keynote - Jörn Piel, ETH Zurich, Switzerland 10:50AM – 11:35AM Orchestra Right & Left New Enzyme Tools From Uncharted Natural Product Space Open Panel Session Chair: Paul Clemons, Broad Institute, USA 11:35AM – 12:15PM Orchestra Right & Left Target Identification and Mechanism-of-Action Studies Using Chemical Biology
12:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing
Session IX – Chemical Proteomics for Drug Target Engagement 1:15PM – 2:45PM Orchestra Right & Left Chairs: Michael Finley and Andrew Zhang Awards Presentation Poster Awards sponsored by ChemBridge and Novartis 2:45PM – 3:00PM Orchestra Right & Left Travel Awards sponsored by Novartis, GlycoNet, STEMCELL Technologies and Beckman Coulter
3:00PM – 3:20PM Coffee Break and Exhibitor Viewing Salon A
Session X– Biosensors and Imaging 3:20PM – 4:50PM Orchestra Right & Left Chair: Jin Zhang
4:50PM – 5:00PM Closing Remarks Orchestra Right & Left
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Welcome Letter Dear ICBS Members and Colleagues, We are particularly proud of this year’s pre-conference Young Chemical Biologists’ Forum, a day organized for We are delighted to welcome you to the Seventh Annual and by young researchers and trainees. For anyone new Conference of the International Chemical Biology Society to the field, the day is intended to deepen their knowledge (ICBS) in the beautiful city of Vancouver. and expertise in different topics so as to enable innovative Once again, this cross-disciplinary conference provides approaches to overcome the current and future challenges an opportunity and forum to bring together international in chemical biology, resulting in mobilizing the next cohort leaders, field drivers, rising stars, trainees and contributors of scientists. Thanks to the faculty and industry seminar from across the global chemical biology community to presenters who volunteered to share their knowledge share technological advances, exciting breakthroughs, with our trainees. and new information. It also provides a forum for creating Our thanks go to the members of the Organizing new collaborations with colleagues from around the Committees who have worked hard to shape the program world, and to discuss the momentum of the field and our and invite speakers whose work is relevant and germane impact on society. to our theme. We also wish to acknowledge Malachite This year’s conference theme is Towards Translational Management Inc. who have kept us on a timeline to Impact. Moving from the bench towards utility in the make sure this conference would happen, and provided clinic, industry or environment; chemical biology has numerous helpful tips and advice along the way. As emerged as a powerful approach to provide proof of always, special thanks go out to our Corporate Sponsors concept in model systems. It allows us to understand and Exhibitors for their generous support and without the relationship between target activity modulation by whom the conference would not be possible. chemical compounds and phenotypic consequences, Thanks to the Keynote speakers, other invited speakers, thus enabling the full potential of our discoveries. oral and poster presenters who together comprise a Chemical biology plays a special role in this translation program rich in content and variety. by developing tools and methodologies to test and study the impact of these discoveries. As we listen to the fine Enjoy your stay in Vancouver, a city unlike any other. A city line up of oral presentations and posters at ICBS2018, with beautiful nature sceneries, a city with unique mix of take a moment to rationalize the theories/hypotheses that cultures, excellent food and energetic life style. We hope each presenter is bringing to the table, as this may be you will have wonderful time and we would like to invite the knowledge that one day may impact your translational you to attend next year’s ICBS conference planned for research. India in November, 2019! As always both young and established scientists will Yours truly, present at this meeting, providing a robust and interactive Tom Pfeifer, PhD, Centre for Drug Research and Development, platform for all to learn, discuss and share throughout the Vancouver, BC, Canada course of the conference. The Rising Stars in Chemical Zaneta Nikolovska-Coleska, MS, PhD, University of Michigan, Biology Awards Session will feature up-and-coming Medical School, Ann Arbor, MI, USA scientists in the field and will, as always, be a source of ICBS2018 Co-Chairs inspiration to all delegates. Overall, this conference will enable the ICBS community to further disseminate its scope and mission and to attract a growing number of members.
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Program PRECONFERENCE: MONDAY, SEPTEMBER 24, 2018 8:00AM – 6:00PM Meeting Registration 8:30AM – 9:00AM Coffee 9:00AM – 5:00PM Young Chemical Biologists’ Forum 9:00AM – 9:10AM Welcome 9:10AM – 11:10AM Expert-Led Forum Chemistry for Biologists – Jonathan Baell, Monash University, Australia 9:10AM – 9:40AM PAINS and Nuisance Compounds: Sorting the Wheat from the Chaff in Bioactive Compounds Assay Development and Screening – Doug Auld, Novartis Institute for Biomedical Research, USA 9:40AM – 10:10AM Considerations in the Design and Interpretation of Assays Applied to Drug Discovery Structural Biology – Scott Lovell, University of Kansas, USA 10:10AM – 10:40AM Gene to Structure: Utilizing X-Ray Crystallography to Support Chemical Biology Insights for Chemical Biology in Industry – Andrew Zhang, AstraZeneca, USA 10:40AM – 11:10AM Chemical Biology in Industry: Small Molecule Driven Target Deconvolution Strategies 11:10AM – 11:25AM Coffee Break 11:25AM – 12:45PM Student-Led Forum, Presenters 1 through 5 Kun Qian, Emory University, USA 11:25AM – 11:40AM Chemical Probe Discovery to Interrogate YAP-TEAD Interaction in The Hippo Signaling Pathway Eline Sijbesma, Eindhoven University of Technology, Netherlands 11:40AM – 11:55AM Disulfide Trapping for the Identification of Selective PPI Stabilizers Ali Nejatie, Simon Fraser University, Canada 11:55AM – 12:10PM Synthesis of Biological Probes Philip Danby, University of British Columbia, Canada 12:15AM – 12:30PM Glycosyl vs Allylic Cations in Spontaneous and Enzymatic Hydrolysis Michael Winzker, Max Planck Institute of Molecular Physiology, Germany 12:30PM – 12:45PM Proteolysis Targeting Chimera (PROTAC) – A New Tool in Drug Discovery 12:45 PM – 1:45PM Lunch on Your Own 1:45PM – 3:00PM Student-Led Forum, Presenters 6 through 10 Sebastian Andrei, Eindhoven University of Technology, Netherlands 1:45PM – 2:00 PM Rational Design of Semi-synthetic Natural Product 14-3-3 PPI Stabilizers Karson Kump, University of Michigan, USA 2:00PM – 2:15 PM Targeting Mcl-1 to Overcome Resistance in Solid Tumors Oluwafemi Akintola, Simon Fraser University, Canada 2:15PM – 2:30 PM Allylic Carbasugars as Substrates for Glycoside Hydrolases Elena Reckzeh, Max Planck Institute of Molecular Physiology, Germany 2:30PM – 2:45 PM Thermal Proteomic Profiling for Target Identification Thomas Garner, Albert Einstein College of Medicine, USA 2:45PM – 3:00 PM Allosteric Modulation and Therapeutic Inhibition of Pro-Apoptotic BAX
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PRECONFERENCE: MONDAY, SEPTEMBER 24, 2018 3:00PM – 3:30PM Tech Talks Creating and Deploying Next Generation Informatics Solutions – What We’ve Learned Along 3:00PM – 3:15PM the Way Whitney Smith, Collaborative Drug Discovery, USA 3:15PM – 3:30PM Antibody-Drug Conjugates Graham Garnett, Zymeworks, Canada 3:30PM – 3:50PM Coffee Break and Exhibitor Viewing 3:50PM – 4:00 PM ICBS Conference Welcome 4:00PM – 4:05PM Keynote Introduction Keynote - Craig M. Crews, Yale University, USA 4:05PM – 4:50PM PROTAC-mediated Protein Degradation: Making Problem Proteins Go Away ICBS Opening Reception and Young Chemical Biologists’ Social – Shark Club, Library Room 5:00PM – 8:00PM Please join us for a drink, hors d’oeuvres, and to network with your colleagues. A cash bar is available.
CONFERENCE DAY 1: TUESDAY, SEPTEMBER 25, 2018 8:00AM – 5:00PM Meeting Registration 8:30AM – 9:00AM Coffee 9:00AM – 9:15AM Welcome Session I - Degradomics 9:15AM – 10:30PM Chair: Shaomeng Wang Shaomeng Wang, University of Michigan, USA 9:15AM – 9:40AM Targeting Gene Transcription by PROTAC Ting Han, National Institutes of Biological Sciences (NIBS), China 9:40AM – 10:15AM Anti-Cancer Sulfonamides Target Splicing by Inducing RBM39 Degradation Via Recruitment to the DCAF15 Ubiquitin Ligase Receptor Eric Fischer, Dana-Farber Cancer Institute, USA 10:15AM – 10:30AM Thalidomide Promotes Degradation of SALL4, a Transcription Factor Implicated in Duane Radial Ray Syndrome 10:30AM – 10:50AM Coffee Break and Exhibitor Viewing Session II – Glyco Chemical Biology 10:50AM – 12:10PM Chair: David Vocadlo David Vocadlo, Simon Fraser University, Canada 10:50AM – 11:15AM Development of Ultra-Sensitive Fret-Quenched Substrates for Quantitative Imaging of Glycoside Hydrolases in Living Cells Jennifer Kohler, University of Texas Southwestern Medical Center, USA 11:15AM – 11:40AM Discovering Host Cell Receptors for Bacterial Toxins Using Photocrosslinking Sugars Frederic Friscourt, University of Bordeaux, France 11:40AM – 11:55AM Sydnone-Modified Monosaccharides for the Metabolic Oligosaccharide Engineering of Living Cells Cristina Zamora, MIT, USA 11:55AM – 12:10PM Human Gut Microphysiological System Illuminates the Role of N-Glycans in Host-Pathogen Interactions of Campylobacter jejuni 12:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing
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CONFERENCE DAY 1: TUESDAY, SEPTEMBER 25, 2018 Open Panel Discussion Chair: Rathnam Chaguturu, iDDPartners, USA Academic/Industry Partnerships to Promote Drug Discovery Through Chemical Biology 1:15PM – 1:55PM Panel: Doug Auld, Novartis USA, Scott Wolkenberg, Merck, Melvin Reichman, Lankenau Institute, Haian Fu, Emory University, Shaomeng Wang, University of Michigan, Rima Al-awar, Ontario Institute of Cancer Research, Yves Auberson, Novartis/EFMC Switzerland 1:55PM – 2:10PM Conference Updates Session III – Computational Chemical Biology 2:10PM – 3:15PM Chair: J.B. Brown J.B. Brown, Kyoto University, Japan 2:10PM – 2:35PM Active Learning of Ligand-Target Interactions to Build Minimally Complex Yet Maximally Predictive Interaction Models Albert Antolin, Institute of Cancer Research, UK 2:35PM – 3:00PM Probe Miner: Objective, Quantitative, Data-Driven Assessment of Chemical Probes Andrey Ivanov, Emory University, USA 3:00PM – 3:15PM Integrated Computational and Experimental HTA Approaches to Discover and Target NSD3-Mediated Protein-Protein Interactions in Cancer 3:15PM – 3:35PM Coffee Break and Exhibitor Viewing Session IV – Emerging and Other Topics 3:35PM – 4:55PM Chair: Sally-Ann Poulsen Sally-Ann Poulsen, Griffith University, Australia 3:35PM – 4:00PM Development of Chemical Probes for Visualising DNA Synthesis in Complex Cellular Systems Milka Kostic, Dana-Farber Cancer Institute, USA 4:00PM – 4:25PM Chemical Probes – Re-thinking our Ecosystem Scott Lovell, University of Kansas, USA 4:25PM – 4:40PM Structure Guided Development of BfrB-Bfd Protein:Protein Interaction Inhibitors: a Novel Target for Antibiotic Development Jeremy Baskin, Cornell University, USA 4:40PM – 4:55PM Impact: a Chemical Strategy for Imaging Phospholipase D and Phosphatidic Acid Signaling Poster Session on Balcony Level: Odd Numbered Presentations 5:00PM – 7:00PM Please join us for hors d’oeuvres and to network with your colleagues. A cash bar is available.
CONFERENCE DAY 2: WEDNESDAY, SEPTEMBER 26, 2018 8:00AM – 5:00PM Meeting Registration 8:30AM – 9:00AM Coffee 9:00AM – 9:05AM Conference Updates
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CONFERENCE DAY 2: WEDNESDAY, SEPTEMBER 26, 2018 Session V – The Chemical Biology – Medicinal Chemistry Continuum 9:05AM – 10:25AM Chair: Yves Auberson Scott Wolkenberg, Merck, USA 9:05AM – 9:30AM Reducing Limitations in the Design of Photoaffinity Labeling Reagents: Development of a Diazirine- Compatible Cross Coupling Reaction Rima Al-awar, Ontario Institute for Cancer Research, Canada 9:30AM – 9:55AM Discovery and Optimization of OICR9429, a WDR5 Chemical Probe Casey Krusemark, Purdue University, USA 9:55AM – 10:10AM In Vitro Selection Assays: New Approaches and Applications in DNA-Encoded Libraries and Activity- Based Probes Masahiko Ajiro, Kyoto University Graduate School of Medicine, Japan 10:10AM – 10:25AM CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 with a Therapeutic Effect for HPV- Induced Neoplasia 10:25AM – 10:45AM Coffee Break and Exhibitor Viewing Session VI – Synthetic Biology 10:45AM – 12:15PM Chair: Jason Micklefield Jason Micklefield,Manchester University, UK 10:45AM – 11:10AM Diversification of Natural and Non-Natural Products Using Engineered Biosynthetic Pathways and Enzymes Michelle Chang, University of California, Berkeley, USA 11:10AM – 11:35AM Synthetic Biology Approaches to New Fluorine Chemistry Kaity Ryan, University of British Columbia, Canada 11:35AM – 12:00PM Building Non-Proteinogenic Amino Acids Florian Mayerthaler, University of Münster, Germany 12:00PM – 12:15PM Understanding Conformational Changes in Nonribosomal Peptide Synthetases 12:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing Session VII – iPSC Chemical Biology 1:15PM – 2:35PM Chair: Steve Haggarty Steve Haggarty, Harvard University, USA 1:15PM – 1:40PM Humanizing CNS Drug Discovery Using Patient-Specific Stem Cells Models Anne Bang, Sanford Burnham Prebys Medical Discovery Institute, USA 1:40PM – 2:05PM Phenotypic Screening of Human Induced Pluripotent Stem Cell Derived Neurons: Balancing Throughput With Relevance Paul Guyett, BrainXell, USA 2:05PM – 2:20 PM ALS Drug Discovery Via High-Throughput Phenotypic Screening Using iPSC-Derived Human Motor Neurons Kimberly Snyder, STEMCELL Technologies, Canada 2:20PM – 2:35 PM Chemical-Induction and Maintenance of Naïve-like Human Pluripotent Stem Cells 2:35PM – 3:10 PM ICBS Business Meeting
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CONFERENCE DAY 2: WEDNESDAY, SEPTEMBER 26, 2018 3:10PM – 3:40PM Coffee Break and Exhibitor Viewing 3:40PM – 5:00PM Rising Stars Rising Stars Session Introduction: ICBS Young Chemical Biologist Awards 2018 3:40PM – 3:45PM Haian Fu, Chair of the Rising Star Selection Committee, Emory University, USA Rising Star 1 3:45PM – 4:10PM Christina Woo, Harvard University, USA Proximity-Directed O-GlcNAc Transferase for Protein-specific O-GlcNAcylation Rising Star 2 4:10PM – 4:35PM Chu Wang, Peking University, China Chemoproteomics Profiling Reveals the Anti-Steatosis Mechanism of a Natural Flavonoid Rising Star 3 4:35PM – 5:00PM Michael Cohen, Oregon Health and Science University, USA Decoding Protein Adp-Ribosylation Networks in Cells Using Chemical Genetic Approaches Poster Session on Balcony Level: Even Numbered Presentations 5:00PM – 7:00PM Please join us for hors d’oeuvres and to network with your colleagues. A cash bar is available.
CONFERENCE DAY 3: THURSDAY, SEPTEMBER 27, 2018 8:00AM – 4:00PM Meeting Registration 8:30AM – 9:00AM Coffee 9:00AM – 09:05AM Conference Updates Session VIII – Synthetic Chemistry 9:05AM – 10:25AM Chair: David Lupton David Lupton, Monash University, Australia 9:05AM – 9:30AM New Reactivity, New Structures...New Functions? Dawei Ma, Institute of Organic Chemistry, China 9:30AM – 9:55AM New Strategies for Synthesizing Bioactive Alkaloids Shinichi Sato, Tokyo Institute of Technology, Japan 9:55AM – 10:10AM Development and Application of Tyrosine Click Reaction Namrata Jain, University of British Columbia, Canada 10:10AM – 10:25AM Synthesis and Application of a Mechanism-Based Inactivator of Endo-(Xylo)Glucanase 10:25AM – 10:45AM Coffee Break and Exhibitor Viewing 10:45AM – 10:50AM Keynote Introduction Keynote - Jörn Piel, ETH Zurich, Switzerland 10:50AM – 11:35AM New Enzyme Tools From Uncharted Natural Product Space Open Panel Session Chair: Paul Clemons, Broad Institute, USA Target Identification and Mechanism-of-Action Studies Using Chemical Biology 11:35AM – 12:15PM Panel Michael Finley, Janssen Research & Development, Bridget Wagner, Broad Institute, Andy Phillips, C4 Therapeutics, Scott Lovell, University of Kansas, Andrew Zhang, AstraZeneca
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CONFERENCE DAY 3: THURSDAY, SEPTEMBER 27, 2018 12:15PM – 1:15PM Lunch on Your Own and Exhibitor Viewing Session IX – Chemical Proteomics for Drug Target Engagement 1:15PM – 2:45PM Chair: Michael Finley and Andrew Zhang Andrew Zhang, AstraZeneca, USA 1:15PM – 1:40PM Elucidating PARP Inhibitor Selectivity Using a PARP Family Affinity Matrix Sherry Niessen, Pfizer, USA 1:40PM – 2:05PM Applying Chemical Biology in the T790M-EGFR Program Andy Philips, C4 Therapeutics , USA 2:05PM – 2:30PM Targeted Protein Degradation: Tools for Target Evaluation and Therapeutic Applications Y. George Zheng, University of Georgia, USA 2:30PM – 2:45PM Bioorthogonal Chemical Probes to Interrogate Protein Acetylation 2:45PM – 3:00PM Poster and Other Awards 3:00PM – 3:20PM Coffee Break and Exhibitor Viewing Session X – Biosensors and Imaging 3:20PM – 4:50PM Chair: Jin Zhang Jin Zhang, Univeristy of California, San Diego, USA 3:20PM – 3:45PM A Suite of New Fluorescent Biosensors for Dynamic Visualization of Cell Signaling in Living Cells Robert Campbell, University of Alberta, Canada 3:45PM – 4:10PM New Colours and Applications of Genetically Encoded Biosensors to Probe Cell Signaling Ellen Sletten, University of California, Los Angeles, USA 4:10PM – 4:30PM Shortwave Infrared Fluorophores for Illuminating Biological Processes In Vivo Poncho Meisenheimer, Promega, USA 4:30PM – 4:50PM Selectivity Differences Between Cellular and Biochemical Kinase Analysis 4:50PM – 5:00PM Closing Remarks
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Thank you to our conference sponsors
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Keynote Speaker Craig Crews Dr. Crews is the Lewis Cullman Professor of Molecular, Cellular and Developmental Biology and holds joint appointments in the departments of Chemistry and Pharmacology at Yale University. He graduated from the U.Virginia with a B.A. in Chemistry and received his Ph.D. from Harvard University in Biochemistry. Dr. Crews has a foothold in both the academic and biotech arenas; on the faculty at Yale since 1995, his laboratory pioneered the use of small molecules to control intracellular protein levels. In 2003, he co-founded Proteolix, whose proteasome inhibitor, Kyprolis™ received FDA approval for the treatment of multiple myeloma. Since Proteolix’s purchase by Onyx Pharmaceuticals in 2009, Dr. Crews has focused on a new ‘induced protein degradation’ drug development technology, PROTACs, which served as the founding IP for his latest New Haven-based biotech venture, Arvinas, LLC. Currently, Dr. Crews serves on several editorial boards and is an Editor of Cell Chemical Biology. In addition, he has received numerous awards and honors, including the 2013 CURE Entrepreneur of the Year Award, 2014 Ehrlich Award for Medicinal Chemistry, 2015 Yale Cancer Center Translational Research Prize, a NIH R35 Outstanding Investigator Award (2015) and the 2017 AACR Award for Outstanding Achievement in Chemistry in Cancer Research.
PROTAC-mediated Protein Degradation: Making Problem Proteins Go Away
Enzyme inhibition has proven to be a successful paradigm for pharmaceutical development, however, it has several limitations. As an alternative, for the past 16 years, my lab has focused on developing Proteolysis Targeting Chimera (PROTAC), a new ‘controlled proteolysis’ technology that overcomes the limitations of the current inhibitor pharmacological paradigm. Based on an ‘Event-driven’ paradigm, PROTACs offer a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins. This approach employs heterobifunctional molecules capable of recruiting target proteins to the cellular quality control machinery, thus leading to their degradation. We have demonstrated the ability to degrade a wide variety of targets (kinases, transcription factors, epigenetic readers) with PROTACs at picomolar concentrations. Moreover, the PROTAC technology has been demonstrated with multiple E3 ubiquitin ligases, included pVHL and cereblon.
www.chemical-biology.org 17 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Keynote Speaker
Jörn Piel Jörn Piel received a PhD in Chemistry at the University of Bonn, Germany, and conducted postdoctoral work with Bradley Moore and Heinz Floss at the University of Washington, Seattle. He then became Research Group Leader at the Max Planck Institute of Chemical Ecology in Jena, Germany, and Associate Professor of Bioorganic Chemistry at the University of Bonn. Since 2013 he is Full Professor of Microbiology at ETH Zurich. Research of his lab focuses on metabolic functions of “microbial dark matter”, the investigation and utilization of new biosynthetic enzymology, and ecology- and genome-based methods of natural product discovery.
New enzyme tools from uncharted natural product space
Most areas of the bacterial tree of life are functionally uncharacterized. These regions include numerous deep-branching taxa that lack cultivated representatives and live in diverse habitats. Our lab uses metagenomic and single-cell-based mining strategies to investigate whether this massive taxonomic and ecological diversity is a resource of metabolic novelty. We have previously reported uncultured symbionts of marine sponges as a rich source of bioactive and biosynthetically unusual compounds.1,2 The talk will present recent insights into the metabolic repertoire of ‘Entotheonella’ sponge symbionts, a “talented” producer taxon with a rich and diverse chemistry comparable to that of streptomycetes. While most of the biosynthetic pathways had no counterparts in known cultured bacteria, functional studies also revealed mechanistically surprising enzymes that expand the chemical space of ribosomal peptide biosynthesis and have widespread homologs in culturable prokaryotes.3-5 Implications for synthetic biology applications will be discussed.
[1] M. Wilson et al., Nature 2014, 506, 58. [2] J.B. Cahn et al., Proc. Natl. Acad. Sci. U. S. A. 2018, 115, 1718. [3] M. F. Freeman et al., Science 2012, 338, 387. [4] M. F. Freeman et al., Nat. Chem. 2017, 9, 387. [5] B .I. Morinaka et al., Science 2018, 359, 779.
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Degradomics
Targeting Gene Transcription by PROTAC Anti-Cancer Sulfonamides Target Splicing by Inducing RBM39 Degradation via Recruitment to the DCAF15 Ubiquitin SHAOMENG WANG Ligase Receptor Warner-Lambert/Parke-Davis Professor in Medicine, University of Michigan, Ann Arbor, Michigan, USA
TING HAN National Institute of Biological Sciences The proteolysis targeting chimera (PROTAC) strategy has Beijing, China emerged as a promising new approach for target validation and for the discovery of potential new therapeutics. In this lecture, I will present our recent efforts to target gene transcription by PROTAC. I will highlight the key differences between protein Recent cancer genome sequencing efforts have identified inhibitors and degraders, as well as the use of the PROTAC mutations in pre-mRNA splicing factors and prompted active strategy to target those truly undruggable targets, including efforts to discover splicing inhibitors as a new strategy for treating transcriptional factors. cancer. Many of the proteins important for splicing, however, have no enzymatic activity and are thus challenging to inhibit via Abstract Author Biography small molecules. We discovered that a class of clinically tested anti-cancer sulfonamides (collectively named as SPLicing Shaomeng Wang has been working on the discovery and inhibitor sulfonAMides (SPLAMs)) functions by promoting the development of novel small-molecules therapeutics for more interaction between the splicing factor RBM39 and the CUL4- than 20 years and is currently the Director of the Michigan DCAF15 E3 ubiquitin ligase, leading to polyubiquitination and Center for Therapeutic Innovation. His research focuses on proteasomal degradation of RBM39. Mutations in RBM39 targeting protein-protein interactions which regulate apoptosis reduce its interaction with CUL4-DCAF15, increase its stability and has resulted in the discovery and advancement of 6 and confer resistance to SPLAMs. RBM39 is essential for pre- compounds into Phase I/II clinical development targeting Bcl-2/ mRNA splicing and inactivation of RBM39 by SPLAMs results in Bcl-xL, MDM2 and IAP proteins. In more recent years, he has aberrant pre-mRNA splicing. Cancer cell lines originating from expanded his research program to target a number of PPIs, the hematopoietic and lymphoid lineages frequently exhibit which regulate epigenetics, including histone readers, writers sensitivity to SPLAMs, and their response to SPLAMs can be and erasers, and have advanced several classes of compounds predicted by the expression levels of DCAF15. Taken together, into advanced preclinical development. our studies reveal RBM39-DCAF15 as the target of SPLAMs, Dr Wang has co-founded four UM start-up companies to help and identify DCAF15 expression as a potential biomarker to bring drugs into clinical development and the marketplace; and guide clinical trials of SPLAMs. has published >280 peer-reviewed papers and is an inventor of 50 issued US patents and international patents. He was elected Abstract Author Biography as Fellow of the National Academy of Inventors in 2014 and is the 2014 University of Michigan Distinguished Innovator. Dr. Han received a BS degree at Tsinghua University in 2006 and a PhD degree at University of Michigan in 2013. He was a Life Sciences Research Foundation Fellow at UT Southwestern before joining NIBS, Beijing as an assistant investigator in 2017.
www.chemical-biology.org 19 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Thalidomide Promotes Degradation of We show that IMiDs disrupt a broad transcriptional network through induced degradation of multiple yet unknown C2H2zinc SALL4, a Transcription Factor Implicated in finger transcription factors, including SALL4, a member of the Duane Radial Ray Syndrome Spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4result in a human developmental condition that phenocopies thalidomide induced birth defects such as absence of thumbs, phocomelia, ERIC S. FISCHER defects in ear and eye development, and congenital heart Dana-Farber Cancer Institute/Harvard disease. We find that thalidomide induces degradation of Medical School SALL4 exclusively in humans, primates and rabbits, but not in Boston, United States rodents or fish. Our study provides a first mechanistic link for the species- specific pathogenesis of thalidomide syndrome. Moreover, the Frequently used to treat morning sickness, the drug thalidomide surprising expansion in substrate repertoire for pomalidomide, led to the birth of thousands of children with severe birth defects. suggest that IMiDs exhibit a large degree of polypharmacology Despite their teratogenicity, thalidomide and related IMiD drugs contributing to both efficacy and adverse effects. In turn, the are now a mainstay of cancer treatment, however, the molecular discovery that IMiDs target an unanticipated large set of C2H2zinc basis underlying the pleiotropic biology and characteristic birth finger proteins with significant differences between thalidomide, defects remains unknown. IMiDs exert their therapeutic effect lenalidomide, pomalidomide and CC-220, suggests that this by recruiting neo-substrates to the CRL4CRBN ubiquitin ligase, chemical scaffold holds the potential to target one of the largest and hence provide clinical proof of concept for the rapidly families of human transcription factors. emerging field of targeted protein degradation. Despite clinical success, and widespread use as PROTAC constituent, the full Abstract Author Biography target repertoire of IMiDs remains elusive. Here we set out to establish the full repertoire of IMiD dependent substrates using Eric Fischer, PhD, received his doctorate in biology from the a large scale proteomics approach. University of Basel (Switzerland) in 2013. In 2015 Dr. Fischer joined the faculty of Harvard Medical School and the Dana-Farber Using multiplexed mass spectrometry-based proteomics, we Cancer Institute to continue his research using a multidisciplinary conduct a large scale screen in a panel of cancer cell lines approach centered on structural biology, chemical biology, and and human embryonic stem cells for targets of thalidomide, proteomics. Research in his lab focusses on understanding lenalidomide, pomalidomide, CC-885, CC-220, and a set of the role that the post-translational modification with ubiquitin degrader/PROTAC molecules. Targets are validated using plays in cellular processes, development and disease, and the biochemical and cell biological tools. development of novel pharmacologic strategies targeting the ubiquitin machinery.
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Glyco Chemical Biology
Development of Ultra-Sensitive Fret- Centre for High-Throughput Chemical Biology (HTCB) at SFU. He received his PhD from the University of British Columbia and Quenched Substrates for Quantitative was a postdoctoral fellow at UC Berkeley. Vocadlo joined SFU Imaging of Glycoside Hydrolases in Living in 2004 where his team focuses on developing new chemical Cells tools to improve our understanding of how carbohydrates influence cell function, with particular emphasis on their roles in neurodegenerative diseases. His pioneering research at the interface of chemistry and glycobiology spans fundamental research in enzymology through to translational preclinical DAVID VOCADLO animal studies. He and his team have been recognized with a Simon Fraser University number of national and international awards. His SFU research Burnaby, Canada was cornerstone technology for co-founding of Alectos Therapeutics, which has since partnered with Merck to advance compounds to the clinic to combat neurodegenerative diseases.
Tunable Förster resonance energy transfer (FRET)-quenched Discovering Host Cell Receptors for substrates are useful for monitoring the activity of various enzymes within their relevant physiological environments. Development of Bacterial Toxins Using Photocrosslinking FRET-quenched substrates for glycosidases, however, has been Sugars hindered by their constrained pocket-shaped active sites. The emerging relevance of this large class of enzymes in a range of human diseases is prompting increased interest in developing technologies to monitor glycosidases in cells and tissues. In this presentation we will discuss our recent progress in the design of JENNIFER KOHLER substrates that overcomes this problem. Among these designs UT Southwestern Dallas, USA we will highlight the invention of Bis-Acetal-Based Substrates (BABS) that bear a hemiacetal aglycon leaving group that tethers fluorochromes in close proximity, also positioning them distant from the active site pocket. Following cleavage of the glycosidic bond, the liberated hemiacetal spontaneously breaks down, Many pathogenic bacteria secrete protein toxins that recognize leading to separation of the fluorophore and quencher. The intact glycosylated receptors on the surface of host cells. While substrates show remarkably efficient quenching efficiency of physiologically significant, the interactions between bacterial greater than 99.5%. These dark to light substrates are efficiently toxins and host glycoconjugates are often low affinity, and turned over by various enzymes in vitro and kinetics experiments therefore difficult to characterize using traditional biochemistry reveal that the first formed hemiacetal product rapidly breaks methods.Methods : To solve this challenge, we developed down, allowing monitoring of enzyme activity. Moreover, the photocrosslinking analogs of monosaccharides, including various substrate designs we describe are also processed sialic acid and N-acetylglucosamine (GlcNAc), and developed in living cells, enabling quantitative monitoring of glycosidase strategies to incorporate these sugars into glycoconjugates activity in their native environment. We expect this strategy to of cultured mammalian cell lines.Results : Activation of the be broadly useful for the development of substrate probes for photocrosslinking functional group leads to covalent crosslinking monitoring glycosidases, as well as a range of other enzymes with neighboring molecules. Crosslinked complexes can having constrained pocket-shaped active sites. be isolated and analyzed by a variety of methods, including immunoblot and proteomics analysis.Conclusion : This Abstract Author Biography approach can be used to covalently crosslink bacterial toxins to their host cell receptors, and more broadly to discover the Dr. David Vocadlo is a professor in the Departments of interaction partners of glycosylated molecules. I will discuss Chemistry and Molecular Biology and Biochemistry. He holds strategies for incorporating photocrosslinking sugars into host a Tier I Canada Research Chair in Chemical Biology at Simon cell glycoconjugates, as well as the application of these tools to Fraser University (SFU) where he is also Co-Director of the define receptors for cholera and pertussis toxins. www.chemical-biology.org 21 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Abstract Author Biography Abstract Author Biography
Jennifer Kohler’s research group develops chemical biology After completing a PhD in chemistry in 2009 on asymmetric methods to understand biological functions of glycosylated organometallic and organic catalysis with Prof. Pavel Kocovsky molecules. Methods include photocrosslinking sugar technology, (University of Glasgow, UK), I transitioned to the field of Chemical which has been used to define glycan-mediated interactions. Biology during my postdoctoral fellowship (2008-2014) in the laboratory of Professor Geert-Jan Boons at the Complex Carbohydrate Research Center (GA, USA), where I developed Sydnone-Modified Monosaccharides for novel chemical probes for imaging the glycome in living cells. the Metabolic Oligosaccharide Engineering In 2014, I obtained a Junior Chair in Chemical Biology from the of Living Cells University of Bordeaux, France (INCIA lab, CNRS UMR 5287) and was recently recruited as a group leader at the European Institute of Chemistry and Biology (IECB) in Bordeaux. I recently received the prestigious CNRS-ATIP-Avenir award. My research FREDERIC FRISCOURT focuses on using organic chemistry to develop novel selective University of Bordeaux - CNRS UM5287, tools that can probe the influence of glycans notably in healthy European Institute of Chemistry and vs diseased states. Biology Pessac, France Human Gut Microphysiological System Illuminates the Role Of N-Glycans in Host- The bioorthogonal chemical reporter strategy, which elegantly Pathogen Interactions of Campylobacter combines the use of metabolically labeled azido sugars and 1,3-dipolar cycloadditions with strained alkynes, is emerging jejuni as a versatile technology for the labeling and visualization of glycans. Advantages of cyclooctyne-based probes encompass their high reactivity, non-toxicity (metal-free conditions) and synthetic modularity. However, azides have been shown to CRISTINA ZAMORA react, to varying degrees, with biological functionalities such Massachusetts Institute of Technology, as thiols. This inherent instability makes the azide functionality USA a precursor for the potential accumulation of secondary metabolites with unknown biological effects. In order to address this limitation, while keeping the advantages of the cyclooctyne framework as the reactive probe, we decided to investigate the A human intestinal immune-competent micro-physiological utilization of other stable 1,3-dipoles as novel reporter. system was employed to the study of NCTC 11168 Campylobacter In this context, we present herein the utilization of 3,4-disubstituted jejuni pathogenicity, through the lens of its N-linked protein sydnones, a singular class of aromatic mesoionic dipoles, as glycosylation (Pgl) pathway. The ability of this Gram-negative novel chemical reporters for the metabolic oligosaccharide enteropathogen to infect and colonize the intestinal trats of avians engineering (MOE) of living cells (Figure). By employing chemical and murine model organisms has been directly linked to the Pgl and enzymatic strategies, the reporter was appended to various pathway, but the exact role of C. jejuni N-glycans in causing monosaccharides in order to study their metabolic invorporation disease in humans is unclear. into glycoconjugates in living mammalian cells. To address this, an accessible tissue construct more closely Introduction of the sydnone moiety onto various metabolic resembling human intestinal epithelia was employed to monosaccharides demonstrated that not only its positioning on characterize several changes in C. jejuni epithelial invasion, the sugar scaffold, but also on the class of carbohydrates, was immunogenicity, and virulence factor composition and function. of prime importance for a successful incorporation of the novel This tripartite co-culture of C2bbe1, HT29-MTX, and macrophage- reporter into cell-surface glycoconjugates. derived mature dendritic cells, results in a mucin layer, intestinal epithelia and associated innate immune component. Due to its high biological stability and specific glycan incorporation, this novel chemical reporter will significantly expand our chemical Pgl knockout ΔpglE, lacking in cell-surface N-linked biology toolbox for the visualization of labeled glycoconjugates. heptasaccharides, was found 100-fold less capable of adhering to and invading this intestinal model in cell infectivity assays.
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Chemokine and cytokine quantification by immunoassay Abstract Author Biography revealed glyco-deficient strains ΔpglD and ΔpglE elicited decreased inflammation of the intestinal epithelium, but increased Dr. Cristina Y. Zamora graduated from Boston College with inflammation of the innate immune component of this tissue a Bachelors of Science degree in Chemistry. In 2008, she construct of up to 25-fold. Virulence-associated outer membrane started her graduate work in the Department of Chemistry at vesicles produced by wildtype and ΔpglE 11168 C. jejuni were Tufts University in the lab of Prof. Krishna Kumar. At Tufts, Dr. shown to have differential composition and function by activity- Zamora developed novel fluorinated reagents for metabolic based protein profiling analysis, with wildtype vesicles able to glycoengineering of cellular proteomes. She also biochemically rescue ΔpglE infectivity to wildtype levels in infection experiments. characterized the activity and ligand preferences of several human sialidases, enzymes differentially regulated in diseases Overall, use of this tripartite system allowed for further such as prostate cancer. In 2014, she joined the lab of Prof. characterization of the multifaceted importance of the Pgl Barbara Imperiali in the Department of Biology at MIT to pathway in C. jejuni host-pathogen interactions within human characterize the relationship between the glycome of human intestinal contexts. We anticipate these methods will be pathogen Campylobacter jejuni and its infectivity in humans. broadly applicable to further studies of C. jejuni and to other From there, her research interests have broadened to targeted enteropathogens of interest. This research was supported by small molecule drug delivery, directed evolution and protein the NIH (R01-GM097241 to B.I., R01EB021908 to L.G.G.) and engineering, and alternative protein scaffold development. DARPA (W911NF-12-2-0039 to L.G.G.).
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www.chemical-biology.org 23 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Computational Chemical Biology
Active Learning of Ligand-Target Tested on GPCR, kinase, nuclear hormone receptor, and CYP450 families, the chemogenomic active learning methodology Interactions to Build Minimally Complex Yet successfully builds highly predictive models of ligand-target Maximally Predictive Interaction Models bioactivity using only 5~20% of the original matrix of activities available. Further, it was tested in simulated prospective prediction experiments and found to demonstrate good performance. A convergence on predictive performance was found early on in J.B. BROWN most datasets, suggesting that the extent of predictability for a Kyoto University Graduate School of given chemical probe development project can be estimated Medicine efficiently from a reduced amount of existing activity data. Kyoto, Japan Active learning represents a novel way to efficiently develop novel chemical probes through use of feedback-driven, dynamic modeling and prediction processes that converge efficiently on Automated chemical screening has ushered in an era which the activity space of interest. generates large ligand-target bioactivity matrices. As the size of the matrices have grown, they have become increasingly Abstract Author Biography more challenging to manually assess, and the use of statistical pattern recognition (often called machine learning or currently J.B. Brown was a post-bachelor researcher in diagnostic “AI”) to analyze the matrices for patterns is becoming common. radiology at the US National Institutes of Health after The recent explosion in interest in deeply-layered neural network completing BS degrees in computer science and math at the architectures (“deep learning”) has generated the impression University of Evansville. His Ph.D. thesis on machine learning in that “bigger means better”, but this leads to a problem in chemoinformatics and bioinformatics was awarded from Kyoto interpretation for chemical biology. Further, big data does not University in 2010. After post-docs in computational biophysics implicitly carry a guarantee of extra benefit. To investigate the and pharmacoinformatics, he became an assistant professor opposite, that is - how small and simple a machine learning can in the Department of Systems Onco-Informatics of the Kyoto be that is yet still predictive, we have developed the technique University Graduate School of Medicine in 2014, and 18 months of ligand-target active learning. later, was awarded an independent position within the same graduate school, where he started the Life Science Informatics We implement classification-type (yes/no) active learning by Research Unit. His research mixes chemoinformatics, clinical separating chemogenomic ligand-target Ki or IC50 bioactivity informatics, and medical bioinformatics, with an emphasis on matrices into strong and weak pairs based on reasonable translational research topics supported by core data processing criteria. A human-intepretable machine learning algorithm and statistical methods. Notably, he has been researching known as the Random Forest employs an ensemble of decision methods in prediction of ligand-target interactions for a decade, trees to identify patterns that are rules for distinguishing between and his recent “small data, simple model” methodologies and the strong and weak binders. The “active learning” terminology results in have received attention in news services such as AAAS’ comes from the strategy of beginning with one strong and one EurkAlert and Japanese newspapers. His current research weak binding pair each, iteratively adding one new ligand-target interests are in identification of small molecule modulators of pair at a time, and subsequently re-updating the decision tree immune response, and human-less fully automatic wet-dry rules needed to separate the strong and weak binders. This bioactivity landscape exploration and knowledge extraction. is in constrast to the “full deck” dumping of all ligand-target J.B. is a member of the Japanese Society for Chemical Biology bioactivities into a single, monolithic model. and the Chemical Society of Japan.
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Probe Miner: Objective, Quantitative, Data- the understanding of drug (poly)pharmacology so that currently available drugs are better employed and the development safer Driven Assessment of Chemical Probes and more efficacious anti-cancer therapeutics.
Integrated Computational and ALBERT A. ANTOLIN Experimental HTA Approaches to Discover The Institute of Cancer Research, London (UK) and Target NSD3-Mediated Protein-Protein London, United Kingdom Interactions in Cancer
Chemical probes are important widely-used reagents in chemical biology for understanding biological systems and ANDREY IVANOV for target validation. However, selection of chemical probes Emory University is largely subjective and prone to historical and commercial Atlanta, United States biases. Despite many publications discussing the aspirational properties of chemical probes and the proposal of ‘fitness factors’ to be considered when assessing chemical tools, scientists often select probes through web-based searchers The recent advances in cancer genomics engaged with the or previous literature that are heavily biased towards older expanded landscape of oncogenic protein-protein interaction and often flawed probes our use vendor catalogues that do (PPI) network have revealed the tumor heterogeneity and not discriminate between probes. Here, we analyse the scope complexity of the oncogenic signaling. To enhance our and quality of published bioactive molecules and uncover large understanding of cancer biology and discover novel therapeutic biases and limitations of chemical tools in public databases that strategies, new effective chemical probes for oncogenic PPIs are need to be urgently addessed and should be always considered urgently needed. Toward this goal we developed a highly robust when using chemical tools. We also provide the online Probe high-throughput PPI screening platform and established a PPI Miner resource (http://probeminer.icr.ac.uk) capitalising on the network of cancer-associated proteins, termed OncoPPi. The plethora of public pharmacological data to enable quantitative, OncoPPi links the cancer driver genes, both oncogenes and tumor unbiased, objective, data-driven assessment of chemical suppressors and allows to identify new tumor dependencies probes and complement expert-curated approaches. We to inform novel strategies for therapeutic interventions. As one assess >1.8m compounds for their suitability as chemical example, the OncoPPi has revealed a new interaction between tools against 2,220 human targets, demonstrating that large- MYC oncogene and NSD3 protein, which plays a critical role in scale public data can contribute to improve chemical probe regulation of chromatin remodeling through a direct association assessment and prioritization to empower researchers in the with BRD4. Inhibition of interactions of NSD3 with MYC and selection of chemical tools for biomedical research and target BRD4 by small molecules would provide new tools to investigate validation. the NSD3-dependent tumorigenesis, and will facilitate cancer drug development. Here we present a novel integrative platform Abstract Author Biography to discover novel chemical probes for NSD3 signaling in cancer. It includes: Dr. Albert Antolin holds a BSc. and MSc. in Organic Chemistry • Computational virtual screeing from Ramon Llull University (Spain). After working as a • Bioinformatics analysis of cancer genomics data molecular modeller in the pharmaceutical industry for two • Protein-protein interaction screening years (Laboratorios Salvat), Albert undertook a European PhD • High-throuput fluorescence resonance energy transfer assay in Pharmacoinformatics at Pompeu Fabra University (Spain). Subsequently, Albert moved to The Institute of Cancer Research We have developed and optimized a time-resolved fluorescence (London, UK) with a Marie Curie Tecniospring postdoctoral resonance energy transfer (TR-FRET) assay to monitor the fellowship. Since 2017, Albert has been a Sir Henry Wellcome interaction of NSD3 and MYC in miniaturized 1536-well ultra- Fellow at the Institute of Cancer Research. His main lines of high-throughput screening (uHTS) format. To identify compound research include the application of computational methods to the scaffolds required for the efficient disruption of NSD3 PPIs, we development, characterisation and selection of chemical probes, have developed novel computational workflow that combines www.chemical-biology.org 25 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
classical cheminformatics approaches with the large-scale of Chemistry, and his Ph.D. in Organic Chemistry and cross-validation virtual screening methods. Based on the Computational Chemistry from Institute of Physiologically Active promising data from our pilot screening, we have launched a Compounds in Russia. Dr. Ivanov carried out his postdoctoral large-scale screening campaign to discover potent and selective research at the National Institute of Diabetes and Digestive and inhibitors of NSD3 interactions. Kidney Diseases of the NIH working on medicinal chemistry and drug design for GPCRs. In 2011 he joined the Emory Chemical Together, the OncoPPi network serves as a powerful resource to Biology Discovery Center and the Department of Pharmacology uncover new cancer vulnerabilities on oncogenic PPIs. OncoPPi at Emory University and now he leads the Computational Network has revealed new mechanism to control MYC-driven Chemical Biology and Systems Pharmacology team at the program through the protein-protein interaction with NSD3. ECBDC. Dr. Ivanov is the recipient of NIH Fellows Award for The integration of our experimental and computational high- Research Excellence, and the Emory University Research throughput approaches provides a robust platform to discover Committee Award, and Emory Winship Cancer Institute Fadlo novel inhibitors of challenging PPIs to facilitate anti-cancer drug R. Khuri Translational Research Award. He represents Emory development. University in the NCI Cancer Target Discovery and Development Network Data Harmonization and Informatics Portal Group Abstract Author Biography (CTD2 D-HIP) and in the CTD2 Dashboard Working Group. Dr. Ivanov has authored or co-authored over 40 manuscripts and 3 Andrey A. Ivanov, Ph.D. is an Assistant Professor in the book chapters. His group utilizes state-of-the-art bioinformatics, Department of Pharmacology and Emory Chemical Biology computational modeling, and systems biology approaches to Discovery Center (ECBDC). He received his Masters degree understand molecular connections among biological pathways in Chemistry from the Moscow State University, Department to facilitate drug target discovery and therapeutic development.
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Emerging and Other Topics
A Small Molecule Binder-Based Approach chemistry approaches to harness the properties of small molecules as tools to address human disease. Her research to Drug Discovery in Chemical Biology goal is to discover new small molecules either as therapies (where current therapies are not available or are not effective) or as chemical probes (that further contribute to understanding complex biology) associated with cancer and infectious disease. SALLY-ANN POULSEN Griffith University, Griffith Institute for A significant outcome of her research has been the Drug Discovery development of new small molecules as chemical probes that Brisbane, Australia enable researchers to track and visualize DNA synthesis across complex mammalian and parasite systems – without chemical probes these systems are otherwise ‘invisible’ to researchers. The application of her novel pro-label methodology drew Fragment based drug discovery (FBDD) is a recently validated inspiration from the pro-drug:drug relationship of medicinal approach to identify small molecules as better chemical starting chemistry and constitutes a critical advance in chemical biology points for drug discovery. Since 2005, fragment screening has capability as it overcomes limitations of other probes, allowing resulted in three FDA approved drugs and more than 30 drug greater applications in biology. candidates in clinical trials. The take-up of FBDD in academia, Sally-Ann has also developed and implemented native state biotech and pharma is growing owing to this success. mass spectrometry as an alternative and complementary Fragment screening is vastly different to high throughput enabling technology in drug discovery, specifically to advance screening (HTS), where hit compounds are relatively strong the detection of small molecules that bind to proteins where binders (KDs in the nM to µM range) commonly detected by detection has been challenging or not possible by mainstream functional output in a biochemical assay. In contrast, fragment technologies. Using this method she has discovered a novel screening is contingent on robust analytical methods to identify inhibitor chemotype for an enzyme family that has been very weak protein−fragment binding interactions with KDs as dominated for more than 70 years by one compound class of low as mM. A number of biophysical techniques have been inhibitor. used to screen fragment libraries for small molecule binding partners for proteins. The most popular techniques to observe these binders include NMR, SPR and X-ray crystallography. The Chemical Probes – Re-Thinking our use of mass spectrometry for fragment screening has remained Ecosystem relatively underexplored. This presentation will highlight the attributes of mass spectrometry as a complementary screening method in fragment-based drug discovery. It will also identify the scope for applying this method to find small molecule binders MILKA KOSTIC that are functionally silent in classical assays. Dana-Farber Cancer Institute REFERENCES Boston, United States [1] Woods, LA; Dolezal, O; Ren, B; Ryan, JH; Peat, TS; Poulsen, S-A. Native State Mass Spectrometry, Surface Plasmon Resonance, and X-ray Crystallography Correlate Strongly as a Fragment Screening Combination. J. Med. Chem. 2016, 59, 2192-2204. Chemical probes, tool compounds that can be used to interrogate [2] Chrysanthopoulos, P.K.; Mujumdar, P.; Woods, L.A.; Dolezal, O.; Ren, B.; intricate functional and mechanistic questions in biology, are Peat, T.S.; Poulsen, S.-A. Identification of a New Zinc Binding Chemotype one of the key contribution that chemical biology as a field by Fragment Screening. J. Med. Chem. 2017, 60, 7333-7349. continues to make to the broader life science and biomedical research communities. As such, chemical biologists have been Abstract Author Biography investing resources and grass-roots efforts into defining what constitutes a chemical probe, and developing guidelines for Sally-Ann Poulsen is Professor of chemistry and Senior characterization and validation. However, although standards Research Leader at Griffith Institute for Drug Discovery, Griffith have emerged, their wide adoption, implementation and University, Brisbane, Australia. Sally-Ann applies modern www.chemical-biology.org 27 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
enforcement are lagging behind. More importantly, in practice, of P. aeruginosa and release of iron is facilitated by a 7 kDa many biologists continue to use “discredited” chemical probes, ferredoxin (Bfd). The structure of the BfrB-Bfd complex revealed also known as historic compounds thus generating unreliable a conserved protein-protein interface (PPI) poised for disruption results and scientific conclusions. The talk will focus on some of the protein-protein interaction by small molecules. We have of the big picture questions surrounding chemical probes, their developed small molecules that block the BfrB-Bfd interaction use and standards, and present some ways in which we can and disrupt iron homeostasis in P. aeruginosa thus providing a address current key challenges. novel route for antibiotic development. Structural information of protein:protein complexes can facilitate Abstract Author Biography the development of lead compounds by providing details regarding specific molecular interactions at the atomic level. As Milka Kostic, Ph.D. is the Program Director, Chemical Biology such, the structure of the BfrB-Bfd complex was determined at Dana-Farber Cancer Institute, a Harvard Medical Schools which permitted analysis of the PPI and the development of a affiliated hospital and research center in Boston, MA, USA. In training set of compounds that could potentially bind to the BfrB this role, she supports a vibrant chemical biology program of surface and inhibit its interaction with Bfd. Fragment-based about 120 scientists (faculty, postdocs, graduate students, drug design (FBDD) methods using STD-NMR were employed staff scientists and technicians), who work tirelessly to develop to identify initial compounds that 1) bind to BfrB and 2) target chemistry-inspired research tools, platforms and strategies, the PPI site. The compound binding mode was determined to make new discoveries in basic biology, as well as translate using X-ray crystallography and guided chemical modification these discoveries into improved clinical practice. Prior to Dana- of the initial fragment into larger compounds with higher binding Farber, Dr. Kostic was the Editor of Cell Chemical Biology affinity for BfrB. and Structure for more than a decade, thus supporting and shaping chemical biology and structural biology communities. The structure of the BfrB-Bfd complex revealed that 12 Bfd Dr. Kostic is a passionate advocate for chemical biology, and molecules bind to BfrB and provided mechanistic insight into iron transport from the BfrB core. Notably, the BfrB surface undergoes its transformative ability to accelerate basic and translational minimal conformational changes and accommodates specific Bfd discoveries on the chemistry-biology-medicine continuum. She residues. The initial fragment compound was found to bind BfrB is also committed to career development and well-being of early with millimolar affinity at the PPI site. A new series of compounds, career researchers, and promoting gender equality in science based on the initial fragment, were found to bind BfrB with low and society. She is an active blogger, and her main creative millimolar affinity and inhibited iron release from BfrB. outlet is cooking and crafting plant-based meals for her friends and family! The structure of the BfrB-Bfd complex revealed a conserved PPI that permitted the development of compounds that block the protein-protein interaction. Initial compounds were identify Structure Guided Development of BfrB- using FBDD methods and were further expanded into more Bfd Protein:Protein Interaction Inhibitors: a potent inhibitors that disrupt iron homeostasis in P. aeruginosa Novel Target for Antibiotic Development thereby providing a novel route for antibiotic development.
Abstract Author Biography
Dr. Scott Lovell has served as Director of the Protein Structure SCOTT LOVELL Laboratory (PSL) at the University of Kansas (KU) for the past University of Kansas decade and has 24 years of experience in the X-ray crystallography Lawrence, United States field. He received his Ph.D. from Purdue University in chemistry where he was trained in X-ray crystallography and studied the structural and optical properties of guest chromophores and biomolecules oriented in organic crystalline matrices. His The iron storage protein bacterioferritin (BfrB), present only in postdoctoral work at the University of Wisconsin-Madison was bacteria, functions to regulate iron concentrations by storing focused on the structure determination of Tn5 transposase:DNA iron and releasing it as needed for metabolic functions. The complexes in an effort to gain mechanistic insight regarding DNA BfrB structure consists of alpha helical subunits that dimerize transposition. Subsequently, he managed an industrial structural and further assemble into a functional 24-mer (440 kDa) biology group at deCODE biostructures, located in the Chicago sphere-like structure that contains an 80 Å diameter core that area, overseeing all aspects of gene-to-structure projects for can store up to 2,000 iron ions. BfrB is required for growth external commercial clients and internal projects, focused on
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drug discovery and development. In addition he assisted in the This approach, which we have termed IMPACT (Imaging maintenance and operation of a synchrotron beamline, operated Phospholipase D Activity with Clickable Alcohols via by deCODE, at the Advanced Photon Source. As the Director Transphosphatidylation), has revealed pools of PLD activity at of the PSL, his current laboratory collaborates with a diverse novel subcellular locations within individual cells and unexpected range of investigators from various academic and industrial heterogeneity of PA signaling across cell populations. We are institutions to obtain structural information of proteins using X-ray currently exploring and will present applications of IMPACT crystallography and utilizes high throughput techniques to rapidly to elucidate novel mechanisms controlling PLD activation in move projects from gene-to-structure. As such, the PSL has normal physiology and in disease. completed over 250 protein crystal structures and coauthored 60 publications. Additionally, Dr. Lovell is a co-investigator on Collectively, our work highlights the importance of using five NIH funded R01 grants aimed at inhibitor development and chemical strategies to directly visualize, with high spatial and manages the structural biology work for these projects. temporal resolution, the subset of signaling enzymes that are active. Impact: a Chemical Strategy for Imaging Phospholipase D and Phosphatidic Acid Abstract Author Biography Signaling Jeremy M. Baskin is the Nancy and Peter Meinig Family Investigator in the Life Sciences and Assistant Professor in the Department of Chemistry and Chemical Biology and the Weill Institute for Cell and Molecular Biology at Cornell University in Ithaca, New York. Born and raised in Montreal, Canada, Jeremy JEREMY M. BASKIN Cornell University received an S.B. degree (Phi Beta Kappa) from the Massachusetts Ithaca, United States Institute of Technology in 2004, majoring in chemistry, minoring in biology and music, and performing research with Stephen Buchwald and Alice Ting. As an NSF and NDSEG predoctoral fellow with Carolyn Bertozzi at UC Berkeley, Jeremy developed Chemical imaging techniques have played instrumental roles in copper-free click chemistry and applied it to image glycans in dissecting the spatiotemporal regulation of signal transduction developing zebrafish, earning his Ph.D. in chemistry in 2009. pathways. Phospholipase D (PLD) enzymes affect cell Jeremy carried out postdoctoral research as a Jane Coffin Childs signaling by producing the pleiotropic lipid second messenger fellow with Pietro De Camilli at the Yale School of Medicine on the phosphatidic acid via hydrolysis of phosphatidylcholine. It cell biology of phosphoinositide lipid metabolism, discovering remains a mystery how this one lipid signal can cause such that the mechanistic basis underlying a genetic disease diverse physiological and pathological signaling outcomes, due featuring aberrant myelination is a defect in phosphoinositide in large part to a lack of suitable tools for visualizing the spatial biosynthesis at the plasma membrane. Jeremy’s independent and temporal dynamics of its production within cells. research program at Cornell, established in 2015, centers on Here, we report a chemical strategy for imaging phosphatidic the chemical biology and cell biology of lipids and biological acid synthesis by PLD enzymes in live cells. Our approach membranes. Using cross-disciplinary approaches, Jeremy’s capitalizes upon the enzymatic promiscuity of PLDs, which we lab pioneers advances in chemical approaches to elucidate show can accept bioorthogonally tagged, or clickable, alcohols novel signaling functions of lipid second messengers including as reporters in a transphosphatidylation reaction. The resultant phosphatidic acid and phosphoinositides. Jeremy’s work has clickable lipids are then fluorescently tagged using an appropriate been recognized by Beckman Young Investigator and NSF bioorthogonal/click chemistry reaction, enabling visualization of CAREER awards as well as his selection as part of the “Future cellular membranes bearing active PLD enzymes. of Biochemistry” special issue of Biochemistry.
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The Chemical Biology – Medicinal Chemistry Continuum
Reducing Limitations in the Design The robustness screen identified reaction conditions that gave good yields of S-M coupling product while minimally perturbing of Photoaffinity Labeling Reagents: the diazirine reporter fragment. This is significant because Development of a Diazirine-Compatible diazirines themselves are reported as competent cross-coupling Cross Coupling Reaction partners. The conditions were found to be highly scalable and exhibited broad scope when applied to a chemistry informer library of pharmaceutically relevant aryl boron pinacol esters. Furthermore, these conditions were used to synthesize a known diazirine-containing probe molecule with improved synthetic SCOTT WOLKENBERG efficiency Merck & Co., Inc. Kenilworth, Univted States Limited synthetic methods have constrained molecular design of PAL probes and results of labeling studies. A newly developed S-M protocol reduces these limitations and provides an alternative to published routes which rely on 3-4 step sequences and/or very long reaction times. Diazirine-based photoaffinity labeling (PAL) reagents are an important class of chemical probes widely used to form stable covalent adducts with proximal binding partners in complex Abstract Author Biography biological mixtures. Despite their prominence, diazirines have Scott Wolkenberg joined Merck Research Laboratories in West been synthesized only by a limited set of methods, imposing Point, PA, in 2003 and is currently Principal Scientist in the significant constraints on the design of diazirine-containing Chemical Biology group. Over the past 14 years, Scott and his PAL probes. Convinced that available synthetic methods were teams have been involved in the design and synthesis of multiple compromising diazirine PAL probe design across a broad range compounds entering preclinical development including Kv1.5 of studies, we investigated expanding the range of methods for blockers for atrial fibrillation, GlyT1 inhibitors for the treatment of their incorporation. cognitive disorders, and a PET imaging agent for early diagnosis Published diazirine PAL probes (n = 212) were analyzed of Alzheimer’s disease. Scott has been a project leader in the according to reaction used for diazirine incorporation and lead optimization space as well as the target validation and lead category of diazirine placement in probe versus unlabeled identification space. Scott has co-authored 43 peer-reviewed parent pharmacophore. Despite the advantages of nesting publications, is co-inventor on 20 patent applications, and has diazirines in the active pharmacophore, this design is the least participated in and organized conferences in the US and abroad. common found in the literature. And, surprisingly, we found a He Chaired the 2015 Gordon Conference on High Throughput near absence of metal-catalyzed cross coupling reactions for Chemistry and Chemical Biology. Scott was born and grew up diazirine PAL probe synthesis. Because biaryls are prominent in in central New Jersey before attending Cornell University; he biologically-active compounds, this suggests synthetic access graduated in 1998 summa cum laude in chemistry with a double is a problem, and we investigated Pd-catalyzed cross coupling major in biology. He received a Ph.D. in organic chemistry from of diazirine-containing aryl halides and boronic acids to form The Scripps Research Institute in La Jolla, CA, where he applied biaryls, i.e. the Suzuki-Miyaura reaction (S-M). inverse-electron demand Diels-Alder reactions in total synthsis in the research group of Dale L. Boger. We conducted 1) an initial fragment-based robustness screen to identify S-M conditions that give high cross-coupling efficiency while not degrading aryl diazirines followed by 2) a survey of pharmaceutically relevant substrates to define the scope and limitations of the method.
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Discovery And Optimization of OICR9429, In Vitro Selection Assays: New Approaches a WDR5 Chemical Probe and Applications in DNA-Encoded Libraries and Activity-Based Probes
RIMA AL-AWAR Ontario Institute for Cancer Research Toronto, Canada CASEY KRUSEMARK Purdue University West Lafayette, United States
At a fundamental level, gene expression is regulated by epigenetic histone modifications. Histone methyltransferases catalyze the The in vitro selection of encoded libraries allows a collective transfer of the methyl group from S-adenosylmethionine to specific querying of function for many molecules simultaneously. Inspired lysine residues on histones. Mixed lineage leukemia 1 (MLL1) is a by natural selection-driven evolution, the signal for this assay is methyltransferase that methylates lysine 4 on histone H3 (H3K4me3) DNA allele frequency change within a population in response and is an important regulator of the haemopoietic system. to selective pressure. This approach has several advantages Dysregulation of MLL1 is often associated with acute myeloid and over assays employed in traditional small molecule screening lymphoid leukemias, making it an attractive therapeutic target. campaigns, such as improved throughput and lower cost. We WD40 repeat protein 5 (WDR5) is a component of the multiprotein present an evaluation of in vitro selection assays with regard to MLL1 complex and is essential for its methyltransferase activity, and their application to discovery from DNA-encoded libraries (DELs) disruption of the WDR5/MLL1 interaction may therefore present and also to selection-based sensing, a new assay approach we a viable therapeutic option for the treatment of MLL-dependent have developed that uses DNA-linked probes to detect enzyme leukemias. Employing a structure-based drug design approach, activity by DNA sequencing or quantitative PCR. we have identified potent and orally bioavailable inhibitors of the WDR5/MLL interaction and demonstrated their efficacy inin vivo Selection assays included affinity purifications with immobilized models. proteins. Using the chromodomains of the chromobox (CBX) 7 and 8 proteins as a model system, we evaluated the robustness of affinity selections with a collection of DNA- Abstract Author Biography linked ligands of known affinity and applied assays with DELs Dr. Al-awar earned a PhD in synthetic organic chemistry of peptidomimetics. Also, we developed selection approaches from North Carolina State University and did a post-doctoral for enzyme substrates for protein kinase (protein kinase A, Src, fellowship at the University of North Carolina at Chapel Hill prior e.g.), protease (caspase), and transferase (farnesyltransferase) to joining Eli Lilly and Company in 1995. In 2002, while still at Eli activities. Crosslinking selections were developed where protein Lilly, Dr. Al-awar was promoted to Head in Discovery Chemistry targets are covalently conjugated to proteins via an active site- Research and Technologies and later served as Head in Route labeling electrophile (fluorophosphonate) and implemented for Selection in Chemical Product Research and Development. In detection of serine hydrolase activity. July 2008 she joined the Ontario Institute for Cancer Research Results indicated critical considerations for sucessful (OICR) to build a drug discovery program. She is now the implementation of selection assays. These included Director and Senior Principal Investigator of OICR’s Drug minimization of background signal, absolute recovery of ligands Discovery Program. Dr. Al-awar also serves as an Associate and substrates, and overall enrichment values. With affinity Professor in the Department of Pharmacology and Toxicology selections, statistical analyses indicated low DNA tag bias and at University of Toronto. suggested that assays are sufficiently robust for both ligand discovery and for determination of quantitative structure-activity relationships. DEL selections yielded novel, selective ligands to CBX8. The development of substrate and crosslinking-based selections allowed a general approach for enzyme activity detection by DNA sequence analysis for the first time. Assays were implemented for detection of several activites in cell lysates and in a screen of 96 kinase inhibitors conducted by www.chemical-biology.org 31 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
DNA sequencing. We examined FIT-039 for its effect on HPV gene expression in HPV+ cervical cancer cells. Primary keratinocytes monolayer In conclusion, this work highlights the potential of the in vitro and organotypic raft culture models were used to evaluate selection assay both for ligand discovery in DELs and as a HPV viral replication and cervical intraepithelial neoplasia (CIN) general enzyme assay platform. phenotypes. Preclinical pharmacokinetics and toxicity tests for FIT-039 were also conducted. The anti-HPV effect of FIT- Abstract Author Biography 039 was further examined in vivo, using HPV+ cervical cancer xenografts. Casey was born and raised in Pike County Illinois and received his B.S. degrees (Chemistry and Crop Science) from the University FIT-039 inhibited HPV replication and expression of E6 and E7 of Illinois-Urbana-Champaign. He obtained his Ph. D. in viral oncogenes, restoring tumor suppressors p53 and pRb Biochemistry at the University of Wisconsin-Madison in the area in HPV+ cervical cancer cells. The therapeutic effect of FIT- of chemical biology under Peter Belshaw, with an emphasis on 039 was demonstrated in CIN model of an organotypic raft new chemical tools for mass spectrometry-based proteomics. culture, where FIT-039 suppressed HPV18-induced dysplasia/ He then conducted postdoctoral training at Stanford University hyperproliferation with reduction in viral load. FIT-039 also with Pehr Harbury and Patrick Brown working on the directed repressed growth of HPV16+, but not HPV- cervical cancer evolution of synthetic chemicals. He began his independent xenografts without any significant adverse effects. Safety and career in 2013 at Purdue University in the Department of pharmacokinetics of FIT-039 were confirmed for systemic and Medicinal Chemistry and Molecular Pharmacology. His group topical routes. works on applications of DNA-encoded libraries for both novel FIT-039 showed potent anti-HPV activity without significant ligand discovery and proteomic activity-based probes, with a toxicity in our preclinical studies. Thus, FIT-039 is expected to focus on protein kinases and chromodomains. Outside of work, be a novel therapeutic for CIN to prevent cervical cancer. FIT- Casey enjoys gardening, basketball, his two young children, 039 is currently evaluated in the phase I/IIa trial for anti-HPV and cats. activity in viral warts and further planned in CIN.
CDK9 Inhibitor FIT-039 Suppresses Viral Abstract Author Biography Oncogenes E6 and E7 with a Therapeutic I graduated Tohoku University development of technology Effect for HPV-Induced Neoplasia in 2005, and received MSc degree in the graduate school of life science in 2007. Then I moved to the Institute of Medical Science of the University of Tokyo, where I received PhD degree for the screening of a novel molecular target and evaluation MASAHIKO AJIRO of small molecule compounds for breast cancer. In 2010, Kyoto University Graduate School of I moved to the National Cancer Institute of NIH in the US as Medicine postdoctoral fellow, pursuing RNA biology for application to drug Kyoto, Japan development. My studies there were focused on RNA splicing regulations associated with disease condition, viral infection, and drug resistance. In 2016, I joined to the Department of Drug Discovery Medicine of the Kyoto University as an Cervical cancer is one of the leading causes of cancer deaths assistant professor to lead a research group for development among women worldwide, and human papillomavirus (HPV) of small molecule compounds targeting viral infection and infection is the etiological cause in more than 95% of cases. splicing-associated genetic diseases. My research goal is to HPV induces tumorigenesis through viral oncogenes, which provide a novel therapeutics for diseases currently without depend on host cell factor cyclin-dependent kinase 9 (CDK9) effective therapeutic options. In cooperation with Dr. Masatoshi for their transcriptional activation. The purpose of this study is Hagiwara, we demonstrated antiviral effect of CDK9 inhibitor to assesses the therapeutic effect of newly developed CDK9 FIT-039 against human papillomavirus (HPV), which is currently inhibitor FIT-039 for cervical malignancy by targeting HPV viral investigated in the phase I/IIa trial for HPV-induced viral warts. gene expression and replication.
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Synthetic Biology
Diversification of Natural and Non-Natural Synthetic Biology Approaches to New Products Using Engineered Biosynthetic Fluorine Chemistry Pathways and Enzymes
MICHELLE CHANG JASON MICKLEFIELD University of California, Berkeley, USA University of Manchester Manchester, United Kingdom
The catalytic diversity of biological systems provides enormous Natural products often require further chemical modification, to potential for the use of living cells to provide new methods for improve their biological activities or physicochemical properties, organic and inorganic synthesis. One fundamentally interesting for therapeutic and other applications. However, many of the chemical phenotype is the ability of Streptomyces cattleya to most promising natural products, particularly the polyketides catalyze the formation of C-F bonds. Because of the unique and nonribosomal peptides are highly complex molecules which elemental properties of fluorine, site-selective fluorination has offer limited opportunity for semi-synthesis, and are invariably emerged as a powerful tool for improving the efficacy of small- inaccessible through total synthesis on the scale required for molecule drugs. Our group is interested in using a synthetic drug development. Consequently, alternative biosynthetic biology approach to expand the scope of fluorinated natural engineering approaches are required, which can enable the products by engineering pathways for their production from the rapid structural diversification and optimisation of promising simple fluorinated building blocks provided byS. cattleya. natural product scaffolds. Synthetic biology, molecular genetics, enzymology and chemical Abstract Author Biography biology methods are used. Michelle is a professor at UC Berkeley in the Departments of In this lecture our recent progress in biosynthetic engineering Chemistry and Molecular and Cell Biology. She received her will be presented. In addition methods for using enzymes from Ph.D. from MIT, working with JoAnne Stubbe and Daniel Nocera, biosynthetic pathways to create non-natural products will be and her postdoctoral training with Jay Keasling at UC Berkeley. described. Her research group works at the interface of enzymology and synthetic biology, with a focus on studying biological New biosynthetic pathways to novel products will be presented. fluorine chemistry, formation of mixed-valent nanomaterials by directional-sensing bacteria, and processes involved in Abstract Author Biography developing synthetic biofuel and monomer pathways. She has received the Dreyfus New Faculty Award, TR35 Award, Jason Micklefield is Professor of Chemical Biology within the Beckman Young Investigator Award, NSF CAREER Award, School of Chemistry and the Manchester Institute of Biotechnology Agilent Early Career Award, NIH New Innovator Award, DARPA at the University of Manchester. He graduated from the University Young Faculty Award, Camille Dreyfus Teacher-Scholar Award, of Cambridge in 1993 with a PhD in Organic Chemistry and 3M Young Faculty Award, Arthur Cope Scholar Award, and then moved to the University of Washington, USA, as a NATO Pfizer Award in Enzyme Chemistry. fellow investigating various biosynthetic pathways and enzyme mechanisms. In 1995 he began his independent research career as a Lecturer in Organic Chemistry at Birkbeck College, University of London before moving to Manchester in 1998. Jason has made diverse contributions at the chemistry-biology interface in the areas of biocatalysis, enzyme mechanisms, biosynthesis, biosynthetic pathway engineering and development of RNA based regulatory tools (riboswitches). www.chemical-biology.org 33 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Building Non-Proteinogenic Amino Acids in Biological Chemistry in 2002. She then carried out graduate studies at MIT, where she worked with Catherine Drennan to solve the X-ray crystal structures of natural product biosynthetic enzymes. From 2008-2010, was a postdoctoral fellow with Bradley Moore at the Scripps Institution of Oceanography at the KATHERINE RYAN University of California at San Diego. She became an Assistant The University of British Columbia Professor in the Department of Chemistry the University of Vancouver, Canada British Columbia in 2011. Her group is interested in elucidating biosynthetic pathways to heterocycle-containing molecules and solving the structures of biosynthetic enzymes.
There are hundreds of naturally occurring amino acids, the majority of which are not incorporated into proteins. Such non- Understanding Conformational Changes in proteinogenic amino acids have diverse structures and biological Nonribosomal Peptide Synthetases activities and could be used to make unnatural peptides. Here I will discuss my group’s work to elucidate biosynthetic pathways to non-proteinogenic amino acids. In vitro reconstitution, mechanistic enzymology, and high- FLORIAN MAYERTHALER resolution protein X-ray crystallography University of Münster Münster, Germany First, I will describe my group’s work on the pathway to L-piperazic acid, a non-proteinogenic amino acid containing a cyclic hydrazine that is incorporated into a variety of non- ribosomal peptides. We discovered that a heme-dependent enzyme catalyzes N-N bond formation to give L-piperazic acid Nonribosomal peptide synthetases (NRPSs) are large modularly from N-hydroxy-L-ornithine.1 Second, I will discuss our discovery organized enzymes that synthesize a plethora of therapeutically of an enzyme pair that converts L-arginine to D-dehydroarginine important peptides. A module consists of multiple discrete in the pathway to the antibiotic indolmycin and highlight the key domains that incorporate specifically one of over 530 different 2 monomers through a sequence of coordinated reactions role of an O2-, pyridoxal phosphate-dependent oxidase. I will furthermore describe our high-resolution X-ray crystallography (1). During the catalytic cycle, the substrates are processed, studies that allowed us to gather ‘snapshots’ during catalysis to covalently linked to the enzyme and then passed on to the next understand how such PLP-dependent oxidases function.3 module. These diverse reactions necessitate that the domains undergo multiple conformational changes that are highly Across both projects, I will describe how we identified these dynamic and still tightly regulated. Currently, little is known enzymes, the in vitro work that allowed us to elucidate their how the structural reconfigurations and interactions within and functions, and the implications for our understanding of enzyme in-between domains are orchestrated (2). Initial studies have catalysis. Furthermore, I will describe potential applications of described the interaction between the peptidyl carrier protein our work in biocatalyst development and drug discovery work. (PCP) and the adenylation domain (3) but dynamic measurements REFERENCES: that elucidate the regulation of the conformational changes 1Du YL, He HY, Higgins MA, Ryan KS (2017) A heme-dependent have been missing. However, this knowledge is required to enzyme forms the nitrogen-nitrogen bond in piperazate. Nat. Chem. understand the coordination of the enzymatic cycle, and thus to Biol. 13, 836-838. precisely engineer NRPS for combinatorial biosynthesis of new 2Du YL, Singh R, Alkhalaf LM, Kuatsjah E, He HY, Eltis LD, Ryan KS products. In order to overcome this shortcoming we applied (2016) A pyridoxal phosphate-dependent enzyme that oxidizes an Förster Resonance Energy Transfer (FRET) spectroscopy to unactivated carbon-carbon bond. Nat. Chem. Biol. 12, 194-199. NRPS by either introducing the fluorophores genetically or using 3Hedges JB, Kuatsjah E, Du YL, Eltis LD, Ryan KS (2018) Snapshots site-specific Michael-like addition with maleimides. This allowed of the catalytic cycle of an O2, pyridoxal phosphate-dependent us for the first time to monitor in real-time and in solution crucial hydroxylase. ACS Chem. Biol., 13, 965-974. interactions between substrates, the adenylation and the PCP domain (4). FRET is a known technique to study protein Abstract Author Biography dynamics (5), but has not been applied to NRPS before due to their size and complexity. Here we report further studies Katherine Ryan received her B.Sc. from the University of Chicago on the dynamics of the domain alternation mechanism of
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the adenylation domain. Using pyrophospatase and different Abstract Author Biography combinations of substrates, we can control the current state of the enzyme and the kinetics of the conformational changes and Florian received his MSc in science from the University of Münster thereby study the directionality of NRPS. These investigations in organic chemistry and biochemistry. He has spent 4 months as will foster our understanding of the NRPS machinery and, a visiting scientist in the Department of Chemistry at Princeton, consequently, facilitate their bioengineering. and at Bayer HealthCare. Florian is currently completing his PhD at the Institute of Biochemistry of the University of Münster (1) S. Caboche et al., J. Bacteriol., 2010 (2) K. Weissman, in the lab of Dr. Henning Mootz where his research focuses on Nat. Chem. Biol., 2015 (3) J. Zettler et al., FEBS J., 2010 (4) characterization of nonribosomal peptide synthetases. J. Alfermann et al., Nat. Chem. Biol., 2017 (5) T. Heyduk, Curr. Opin. Chem. Biol., 2002
Notes
www.chemical-biology.org 35 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada iPSC Chemical Biology
Humanizing CNS Drug Discovery Using pathways. Continued expansion of a ‘living library’ of patient- specific iPSC models coupled to electronic health records Patient-Specific Stem Cells Models and deep clinicopathological phenotyping along with further methodological optimization and development of improved disease-relevant, quantitative assays have the potential STEPHEN J. HAGGARTY to advance multiple phases of novel target discovery and Harvard Medical School, Department therapeutic development for CNS disorders. of Neurology, Chemical Neurobiology Laboratory, Massachusetts General Hospital Abstract Author Biography Boston, United States Dr. Stephen J. Haggarty is an Associate Professor of Neurology at Harvard Medical School, an Associate Neuroscientist at Advances in a combination of disciplines—chemical biology, Massachusetts General Hospital, and Director of the MGH human stem cell biology, and human genetics—are impacting Chemical Neurobiology Laboratory in the Center for Genomic both our understanding of fundamental human disease biology Medicine. Dr. Haggarty is also a Senior Associate Member of and our ability to discover next-generation pharmacological the Broad Institute and Affiliate Faculty Member of the Harvard agents targeting the root cause of disease. Perhaps nowhere Stem Cell Institute. He completed his PhD in the Department of are these advances most significant and critically needed than Chemistry & Chemical Biology at Harvard University, and joined the area of central nervous system (CNS) disorders. While there the faculty of HMS/MGH in 2006. Dr. Haggarty was named has been an explosion of new genetic information revealing the Stuart & Suzanne Steele MGH Research Scholar in 2017. insight into their etiopathogenesis, major gaps exist in the Dr. Haggarty’s research program operates at the interface of translational of these observations to a deep understanding of neurology and psychiatry with a focus on dissecting the role of the underlying disease biology, the discovery and validation of neuroplasticity and resiliency in health and disease. His efforts are new targets for disease treatment or prevention, and improved guided by knowledge emerging from human genetics regarding diagnoses. the root causes of disease and have led to the discovery of novel chemical probes targeting the regulation of neurotrophic In this context, patient-derived, induced pluripotent stem cell factor signaling, epigenetic regulation of neuronal gene (iPSC) models are increasingly recognized as providing robust expression, neurogenesis, synaptogenesis, and proteostasis and scalable ex vivo models systems of both rare and complex networks. A major emphasis of his is the use of reprogramming polygenic CNS disorders. Such ex vivo models of human technology to create patient-specific, induced pluripotent stem disease, combined with powerful omic technologies, pathway- cells (iPSCs) as ex vivo models of neurogenetic disorders. focused phenotypic screening, and high-content, quantitative The ability to differentiate human iPSCs into neural networks imaging, enable systematic probing of the physiology and with the capacity to form synapses and regulate genes in an biochemistry of previously inaccessible cell types at specific activity-dependent manner provides powerful new avenues for stages of CNS development. Moreover, similar to other areas studies of neuroplasticity, for understanding the neurobiology of medicine, recent findings suggest the value of a paradigm of human disease, as well as for addressing the challenging where therapies are first tested ex vivo for target engagement goal of discovering novel targets and next-generation, disease- and disease-relevant functional signatures in patients’ cells modifying therapies using the principles of genomic medicine. to stratify patient populations prior to testing in vivo in formal clinical trials. Here, I will provide select examples of programs within the Chemical Neurobiology Laboratory at Harvard Medical School/ MGH seeking to characterize patient-specific iPSC models of neurodegenerative and neurodevelopmental disorders and identify targets for developing novel disease-modifying therapeutics. Specific examples of small-molecule screens will include efforts to probe mechanisms of neuroresiliency and proteostasis, as well as large-scale screens of neurogenesis
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Phenotypic Screening of Human Induced to joining SBP she served as Director of Stem Cell Research at ViaCyte Inc, where she focused on developing stem cells as a Pluripotent Stem Cell Derived Neurons: source of pancreatic cells to treat diabetes. Dr. Bang received Balancing Throughput With Relevance a B.S. from Stanford University, a Ph.D. in Biology from UCSD, and was a post-doctoral fellow at the Salk Institute.
ALS Drug Discovery Via High-Throughput ANNE BANG Sanford Burnham Prebys Medical Phenotypic Screening Using iPSC-Derived Discovery Institute Human Motor Neurons La Jolla, United States
The lack of human-specific pre-clinical models of neurological PAUL GUYETT disease is likely a factor that contributes to low rates of new BrainXell, Inc. therapies entering clinical trials. Human induced pluripotent Madison, United States stem cells (hiPSC) based models could potentially be used to address this void and aid in the development of clinically useful compounds. hiPSC are scalable, circumvent issues of species specificity, and allow interrogation of differentiated features of Amyotrophic lateral sclerosis (ALS) is a neurodegenerative human neural cell-types not reflected by immortalized lines. disease primarily affecting motor neurons. Unfortunately, there Importantly, they can also carry disease traits in the context of are only two drugs approved to treat the condition, neither of specific human genetic backgrounds, offering an opportunity to which increases patient survival by more than a few months. better stratify patients and identify drug targets. This sobering reality highlights the urgent need for new ALS Development of technology platforms to interrogate hiPSC- therapeutic development, which has been plagued by high failure derived neural cell types with relatively high-throughput will rate of drug candidates during clinical trials. This high failure be advantageous not only for drug screening, but also for rate suggests that pre-clinical screening strategies need to be phenotype discovery, allowing testing of multiple patient derived re-evaluated. One of the markers of disease in ALS patients is lines, and variables, such as timing and dose response to the aberrantly low expression of neurofilament light chain (NFL) in therapeutic agents, pathway modulators, and stress inducers. motor neurons. Further, recovery of NFL to normal levels prevents Towards this goal, we have been working to develop platforms hallmark phenotypic changes in ALS neurons. Therefore, we to assess fundamental aspects of neuronal morphology and wanted to establish a clinically relevant screening platform to physiology, providing a basis for further development of more identify compounds that return expression of NFL to normal complex phenotypic readouts and compound screens based levels in ALS patient derived motor neurons. on patient specific hiPSC-derived neurons. We will discuss a At BrainXell, we established new technologies to rapidly large-scale image based high-content compound screen of differentiate ALS patient induced pluripotent stem cells (iPSCs) neuronal morphology. In addition, we will present our progress into large quantities of neurons. We then used genome editing developing multi-electrode array (MEA) assays to monitor techniques to endogenously fuse NFL with a nanoluciferase electrical activity, model synaptic plasticity, and evaluate drugs (NLuc) reporter, thus enabling a high-throughput screening on networks of hiPSC-derived neurons. (HTS) system that monitors the expression levels of NFL after 72 h exposure to each compound. The assay was adapted to Abstract Author Biography meet HTS requirements, including: large batch sizes, 1536-well format, minimal well-to-well variation, short-term culture, plating Dr. Anne Bang joined the Sanford Burnham Prebys Medical by automated dispenser, and low reagent volumes. Applying Discovery Institute in June 2010 as Director of Cell Biology at a quantitative HTS approach, we screened the LOPAC, NPC, the Conrad Prebys Center for Chemical Genomics, a state- and MIPE libraries (>6,000 compounds) in a dose dependent of-the-art drug discovery center. Her current research efforts manner. Compounds that increase NFL expression by 50% (to are directed at developing patient-specific, induced pluripotent approximately normal levels) were considered hits. stem cell (iPSC)-based disease models for drug discovery, with an emphasis on neurological and neuromuscular disease. Prior From these screens we identified 50 hit compounds that are www.chemical-biology.org 37 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
currently going through secondary validation. Preliminary data mTeSR™1 or TeSR™-E8™, are first exposed to a histone looks promising. For example, one of these hits restores normal deacetylase inhibitor and then subsequently transitioned and expression of NFL with no observed toxicity. maintained in NaïveCult™ Expansion Medium. This process is carried out on hPSCs seeded on inactivated murine fibroblasts In conclusion, we have developed technologies to generate and under 5% oxygen conditions. Using our optimized protocol, motor neurons from ALS patient iPSCs and demonstrated their we generated multiple naïve hPSC lines (n=5) from primed application to increase clinical relevance of high-throughput drug human embryonic stem cell lines Shef6, H1 and H9 and human discovery. Using this approach we can screen large libraries of induced pluripotent stem cells WLC-1C and STiPS-F016. We small molecules to identify hit ALS therapeutics. also tested the ability of naïve hPSCs maintained in NaïveCult™ Expansion Medium to differentiate into endoderm, mesoderm Abstract Author Biography and ectoderm by using the STEMdiff™ Definitive Endoderm Kit, STEMdiff™ Mesodermal Induction Medium and STEMdiff™ Paul Guyett is a Postdoctoral Scientist at BrainXell in Madison Neural Induction Medium kits, respectively. Wisconsin. He graduated from Washington State University in 2011 with a Ph.D. in Molecular Biosciences studying the During the transition to naïve hPSCs, early passage colonies biophysical contributions of hydrophobic amino acids to undergo robust morphological changes characterized by heterodimeric protein folding. Paul then worked with Kojo Mensa- the acquisition of a domed phase-bright morphology on a Wilmot at University of Georgia using genetics and chemical background of heterogeneous cellular differentiation. By passage biology to investigate protein kinase signaling pathways in the 5, cultures become increasingly homogenous with colonies parasitic African Trypanosome. This work was then translated typically demonstrating uniform domed and phase-bright into a thriving academic drug discovery program. Paul was morphology and low levels of background differentiation. Naïve then recruited by BrainXell to progress their ALS drug discovery hPSC lines, in addition to displaying a naïve cellular phenotype, program. Paul’s interests are multidisciplinary, and center on the also demonstrate the expected signature gene expression use of small-molecules to perturb biological systems as both profiles associated with naïve pluripotency. Our results scientific tools and potential therapeutics. demonstrate that these cells are capable of differentiation to all somatic cell lineages with optimal results following a minimum Chemical-induction and Maintenance of of 21 days of re-priming in TeSR™-E8™ or mTeSR™1. Naïve-Like Human Pluripotent Stem Cells In summary, we have demonstrated robust establishment and expansion of chemically-induced and maintained naïve hPSCs using NaïveCult™ Induction Kit and Expansion Medium.
Abstract Author Biography KIMBERLY SNYDER STEMCELL Technologies Inc. Kimberly Snyder obtained her Master of Science in Experimental Vancouver, Canada Medicine at the University of British Columbia in 2014. She completed her studies under the supervision of Dr. Kelly McNagny studying the role of the CD34-related sialomucin, podocalyxin in metastatic breast cancer. Furthermore, in Human pluripotent stem cells (hPSCs) are traditionally captured a collaboration with the Centre for Drug Research and in a primed pluripotent state when isolated from early-stage Development (CDRD), She used pre-clinical mouse models to embryos. Human naïve cells have been previously obtained evaluate candidate therapeutic antibodies against podocalyxin by overexpression of transcription factors regulating key to block the growth and metastasis of established tumors. In pathways controlling pluripotency. Here we demonstrate how 2014, Kim was recruited to STEMCELL Technologies Inc. and is the NaïveCult™-t2iLGö media system uses chemical inhibitors a Scientist in R&D working in the Pluripotent Stem Cell Biology of histone acetyltransferases in combination with Wnt signalling Team. In her role, Kim primarily works on media development modulators and small molecule inhibitors of mitogen-activated for the reversion and maintenance of primed human pluripotent protein kinase kinase (MEK) and protein kinase C (PKC) to induce stem cells to the naive-like state. hPSCs to adopt a naive-like state. Further, this media system was developed to support the continuous robust expansion of naïve-like hPSCs. Chemical generation of naïve hPSCs using NaïveCult™ Induction Kit involves sequential steps in which hPSCs, maintained in
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Synthetic Chemistry
New Reactivity, New Structures...New New Strategies for Synthesizing Bioactive Functions? Alkaloids
DAVID LUPTON DAWEI MA Monash University Shanghai Institute of Organic Chemistry Melbourne, Australia Shanghai, China
Discoveries in chemical synthesis often provide access to new In this lecture we report our recent efforts toward the total materials, or previously inaccessible due to inefficiencies in synthesis of alkaloid by developing new synthetic strategies, chemical synthesis. This pipeline, connecting novel molecular which include total syntheses zaitine and navirine C by using a structures to discoveries in application focused chemistry, chelation-triggered conjugate addition to a,b-unsaturated nitrile will remain integral in the future as increasingly challenging and oxidative-dearomatization/Diels-Alder cycloaddition as the problems in, for example, energy and health, demand viable key steps; a short and convergent route for assembling gelsedine universal solutions. alkaloids, and total synthesis of lipidilectine B by installing its spiro indoline and lactone units through a manganese(III)- Studies in my research group are focused around the discovery mediated oxidative cyclization of a 1,2,3-trisubstituted indole. and use of catalytic reactions to deliver novel molecular structures. In this talk a summary of recent discoveries in organocatalysis,1 transition metal catalysis,2 and biocatalysis3will Abstract Author Biography be provided focusing on the ways that new synthesis can Dr. Dawei Ma received his PhD in 1989 from Shanghai Institute address unmet challenges in society. of Organic Chemistry (SIOC), and did his postdoctoral studies at the University of Pittsburgh and Mayo Clinic. He returned Abstract Author Biography to SIOC in 1994, and was appointed as research professor in 1995. He is presently the deputy director of SIOC and an David W. Lupton graduated with a Bachelor of Science (Honors, associate editor of Journal of Organic Chemistry. His research 1st class) in 2001 (University of Adelaide) before being awarded interests currently focus on the development of new synthetic a Doctorate of Philosophy for studies under the supervision methodologies, the total synthesis of complex natural products of Professor Martin G. Banwell (Australian National University) and their SAR and action mode studies, as well as the discovery in 2005. Dr. Lupton then undertook a postdoctoral fellowship of small modulators for target proteins and special biological with Professor Barry M. Trost (Stanford University, USA) as a Sir processes. Keith Murdoch fellow of the American Australian Association. In 2007 he returned to Australia to take up an academic appointment at Monash University in Melbourne, receiving an Australian Research Council Future Fellowship in 2011. In addition, in 2010 he received the Athel Beckwith Lectureship of the Royal Australian Chemical Institute (RACI), and in 2012 a Thieme journal award of the Organic Editorial Board. In 2013 he received the Rennie Medal of the RACI. In 2015 he received the Alexander von Humboldt Ludwig-Leichardt Awardee for studies with Professor Herbert Mayr. He has served as the Associate Head of Research within the School of Chemistry and was promoted to Professor in 2018.
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Development and Application of Tyrosine Abstract Author Biography Click Reaction Shinichi Sato received his B. Sc. Degree in 2006 from Meiji Pharmaceutical University, and his Ph. D. degree in 2011 form University of Tokyo (Professor Yuichi Hashimoto). He spent one year in Professor Carlos F. Barbas’s group at The Scripps SHINICHI SATO Research Institute as a JSPS fellow. He joined the Department Tokyo Institute of Technology of Chemistry, Faculty of Science, Gakushuin University as Kanagawa, Japan an assistant professor in 2012. He is currently an assistant professor in Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology. He was awarded in Ajinomoto Award in Synthetic Organic Chemistry and The Pharmaceutical Society of Japan Kanto Branch Young The chemical modification of proteins with synthetic probes is an Scientist Award. important technique in chemical biology, protein-based therapy, and material science. In addition to conventional modification methods that target nucleophilic amino acid residues such Synthesis and Application of a Mechanism- as lysine and cysteine residues, alternative methods that Based Inactivator of Endo-(Xylo)Glucanase can modify other amino acid residues, such as tyrosine or tryptophan residues, have attracted immense attention recently. In the attempt to modify native proteins, we developed tyrosine- specific bioconjugation reaction. NAMRATA JAIN Based on the report by Barbas et al. (JACS 2010) in which University of British Columbia diazodicarboxyamide compound modifies tyrosine via ene- Vancouver, Canada type reaction, we thought that a reactive diazodicarboxyamide would enable us to modify the tyrosine residue efficiently. In order to generate highly reactive diazodicarboxyamide in situ, we synthesized several hydrazide derivatives (CO-NH-NH- CO), the precursors of diazodicarboxyamide (CO-N=N-CO), Glycoside Hydrolases (GHs) are a major class of carbohydrate- and evaluated as the tyrosine modifier using various catalysts, active enzymes (CAZymes) capable of catalysing glycosidic bond including peroxidase, in the presence of a tyrosine-containing cleavage. The discovery and characterization of GHs targeting peptide. The optimized reaction conditions by the peptide complex carbohydrates is of significant interest in the field of experiments were applied to the protein chemical modification. biomass utilization. Xyloglucan is a complex polysaccharide In order to clarify the modified residues on the protein, enzymatic rich in the cell walls of all terrestrial plants, making it a valuable digestion of the modified protein with trypsin and LC-MS and source of fermentable carbohydrates. As such, the discovery MS/MS analyses were carried out. of xyloglucan-active enzymes is an active area of research. Small molecule glycomimetic mechanism-based covalent We found that the N-methylated luminol derivative was activated inhibitors are valuable tools to probe the active site of GHs, by horseradish peroxidase (HRP), efficiently inducing covalent yielding valuable information about specificity and mechanism. bond formation with tyrosine residue. The potential mechanism-based inhibitor XXXG(2F)-β-DNP was This labeling reaction selectively proceeded only at a tyrosine synthesized from the xyloglucan-derived heptasaccharide XXXG residue among all natural amino acid residues. Furthermore, the (Xyl3Glc4), which was produced from tamarind kernel powder surface-exposed tyrosine residues underwent modification with enzymatically. It was then tested as an active-site label against N-methylated luminol derivative more efficiently than internal five endo-(xylo)glucanases of differing origins. Detailed inhibition tyrosine residues. kinetic parameters for a representative, highly specific GH5 endo- (xylo)glucanase from the soil saprophyte Cellvibrio Japonicus We found that the N-methylated luminol derivative was (CjGH5D) were determined. Additionally, X-ray crystallography efficiently activated by HRP to induce covalent bond formation was used to examine the three-dimensional structure of the with a tyrosine residue. This highly efficient tyrosine-specific XXXG(2F)-CjGH5D covalent glycosyl-enzyme intermediate. modification method with high provides an attractive strategy Results : We were able to produce a stereochemically pure not only for the modification of peptides but also for protein XXXG(2F)-β-DNP via a chemo-enzymatic synthesis. Through modification and immobilization. intact mass spectrometry, kinetics, and crystallography, we demonstrated that this compound is indeed an inhibitor of
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“retaining” endo-(xylo)glucanases, and specifically labels Abstract Author Biography the catalytic nucleophile. Using protein crystallography, we subsequently directly mapped enzyme-substrate interactions in Namrata Jain received her Bachelor of Technology (B. Tech.) CjGH5D of a covalent inhibitor complex vis-à-vis a previously degree in Chemical Science and Technology from the Indian determined XXXG-N-bromoacetyl active-site-directed affinity Institute of Technology Guwahati in 2012. Thereafter, she ligand complex. The synthesis of the heptasaccharide worked with Prof. Elizabeth Gillies at Western University in XXXG(2F)-β-DNP has enabled the production of a structurally Canada and completed her M.Sc. in chemistry in 2014 on the complex 2-deoxy-2-fluorosugar mechanism-based inactivator. synthesis of carbohydrate functionalized dendrons for use as Possessing specificity advantages over analogous xyloglucan multivalent scaffold and in self-assembled structure. oligosaccharide affinity-based inhibitors3, we anticipate that Subsequently, she joined Prof. Harry Brumer’s group at the XXXG(2F)-β-DNP may find continued use in structure-function Michael Smith Laboratories in the University of British Columbia analyses of endo-(xylo)glucanases from diverse GH families. to work on the synthesis of oligosaccharide-based covalent Attia, M. A. & Brumer, H. Curr. Opin. Struct. Biol. 40, 43–53 (2016). inhibitors of carbohydrate active enzymes (CAZymes) capable of yielding valuable information about the function, mechanism Attia, M. A. et al.. Biotechnol. Biofuels 11, 45–61 (2018). and specificity of individual glycoside hydrolases (GHs) by Fenger, T. H. & Brumer, H. ChemBioChem 16, 575–583 (2015). probing their active site and thus facilitating the understanding of specific pathways utilized by GHs in plant biomass degradation.
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www.chemical-biology.org 41 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Chemical Proteomics for Drug Target Engagement and Identification
Elucidating PARP Inhibitor Selectivity Using Abstract Author Biography a PARP Family Affinity Matrix Andrew Zhang is an Associate Principal Scientist in the Chemical Biology Group at AstraZeneca. He joined AstraZeneca in 2013 with research interests in target deconvolution, particularly using chemical proteomics and orthogonal methods for identifying ANDREW ZHANG targets, profiling selectivity, and confirming engagement. AstraZeneca Previously, he has conducted research at the interface Boston, United States between small molecules and antibodies, on small molecule immunomodulators as well as antibody-drug conjugates. He obtained a Bachelors of Science degree in Chemistry and a Bachelors of Arts degree in Molecular and Cell Biology from the University of California, Berkeley, and completed his PhD The poly(ADP-ribose) polymerase (PARP) family consists of training with Professor David Spiegel at Yale University. Prior to enzymes implicated in DNA damage response (DDR), and joining AstraZeneca, he spent one year in the Drug Discovery PARP inhibitors have seen widespread clinical application for Program at the Ontario Institute for Cancer Research (Toronto, cancers presenting deficiencies in homologous recombination. Canada) as a postdoctoral fellow. Identification of a comprehensive profile of targets inhibited by PARP inhibitors, particularly understanding their pan- PARP selectivity, is important generating hypotheses around Applying Chemical Biology in the T790M- differences in efficacy and toxicity. Immobilized chemical EGFR Program probes, including family affinity matrices, are very useful for probing target engagement and selectivity in a biologically relevant setting. We generated an affinity matrix consisting a single promiscuous SHERRY L NIESSEN phthalazinone analogue capable of enriching up to 15 of the Pfizer 17 known PARP enzymes, including those implicated in DDR La Jolla, United States (PARPs 1-3) and gut toxicity (Tankyrase). Through reverse competition of PARPs binding in MDA- MB-436 BRCA-mutant lysate against the affinity matrix followed by a mass spectrometry-based readout, we profiled 5 clinical To enable a more complete understanding into the mechanism inhibitors (niraparib, olaparib, rucaparib, talazoparib, veliparib), of action of covalent EGFR inhibitors we specifically explore showing their distinct PARP selectivity profiles in a disease the proteome-wide reactivity of a series of third-generation relevant context. In-depth statistical analysis of dose response T790M-EGFR inhibitors in human cancer cells and animal profiles performed with our in-house developed tool named models through the development and application of chemical DOSCHEDA (Downstream Chemoproteomics Data Analysis) probes and quantitative mass spectrometry-based proteomic identified putative binding partners and their interactions with methods. We identify that each T790M-EGFR inhibitor has PARP1. a distinct off-target labeling profile in cancer cells which is We have developed a chemical proteomics assay to profile the centered on the engagement of proteins with functional and selectivity of PARP inhibitors in biologically relevant settings ligandable cysteines. These studies highlight the importance across the PARP family and applied this towards understanding of performing global analyses of drug action in living systems the pan-PARP selectivity of clinically relevant PARP inhibitors, to identify targets and off-targets that may impact efficacy and generating hypotheses around their observed phenotypes in safety. vitro and in vivo.
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Abstract Author Biography of small molecules that direct the machinery of the ubiquitin- proteasome system to selectively degrade disease-relevant Sherry Niessen obtained her PhD at Scripps Research Institute proteins for therapeutic benefit. (TSRI) in the lab of Dr. Benjamin Cravatt, and remained as a Scipps staff scientist at The Center for Physiological Proteomics Before joining C4 Therapeutics, Andy was Senior Director, prior to joining Pfizer in 2012 where she is currently a Principal Center for Development of Therapeutics at the Broad Institute scientist, Worldwide Medicinal Chemistry. Sherry is a chemical of MIT and Harvard, where he led overall therapeutic efforts biologist with 12 years of interdisciplinary research experience and provided strategic leadership for a number of major bridging chemical biology, proteomics (applying; LTQ, Orbitrap, partnerships. Previously, he was a Full Professor of Chemistry Velos, QE), metabolomics (applying; QQQ, qTOF), cell and at Yale University, where he received the ACS Cope Scholar molecular biology. Award for his research accomplishments, which included the development of small molecules aimed at modulating Sherry’s research is currently focused on the identification ‘undruggable’ targets. Prior to this, he was a Full Professor and characterization of therapeutic protein targets of small of Chemistry and Biochemistry at the University of Colorado molecules. at Boulder, where his efforts in complex molecule synthesis Education: 2005-2008 The Scripps Research Institute (TSRI), and targeting protein-protein interactions garnered a number La Jolla, USA Ph.D. in Cell Biology and Chemical Physiology of awards, including an Alfred P. Sloan Research Fellowship, Laboratory of Dr. Benjamin Cravatt 2000-2004 McGill an Eli Lilly Grantee Award, and a National Science Foundation University, Montreal, Canada M.Sc. in Experimental Medicine CAREER Award. Andy received a B.Sc. (Hons) in biochemistry Laboratory of Dr. Guy Sauvageau 1995-2000 Simon Fraser and a Ph.D. in biochemistry and chemistry from the University University, Burnaby, Canada B.S. in Biochemistry Positions: of Canterbury in New Zealand and completed a postdoctoral Pfizer Principal scientist (R5), Worldwide Medicinal Chemistry, fellowship in organic chemistry at the University of Pittsburgh. La Jolla (2012-current). The Scripps Research Institute 1) Staff Scientist, The Center for Physiological Proteomics (CPP) (2008- Bioorthogonal Chemical Probes to 2012). Interrogate Protein Acetylation Targeted Protein Degradation: Tools for Target Evaluation and Therapeutic Applications Y. GEORGE ZHENG University of Georgia Athens, United States
ANDREW J. PHILLIPS C4 Therapeutics Watertown, United States Acetylation of lysine residues is one of the most important posttranslational modifications that diversify protein functions by changing protein stability, location, and protein-protein interaction. This process is mediated by Lysine acetyltransferases (KATs). Although housands of acetylated lysine residues have This talk will provide a brief introduction to targeted protein identified, there is a missing link connecting the compositions degradation and will highlight two specific applications of of the cellular acetylome networks to the enzymatic activities this rapidly emerging technology: the degradation of BET of different KAT members. The outstanding challenge is how to bromodomain proteins for therapeutic impact in leukemias and dissect the subacetylomes of individual KATs and address their the introduction of ATAG – an ‘open-source’ toolkit designed functions on the proteomic scale. to enable the chemical biology community to evaluate the degradation of targets both in vitro and in vivo. We have explored a bioorthogonal profiling of protein acetylation strategy to label substrates of KAT enzymes. In this strategy, engineered KAT enzymes were created in conjugation with Abstract Author Biography matching synthetic acetyl-CoA molecules to form orthogonal Andy Phillips is President and Chief Executive Officer of C4 labeling pairs for KAT substrate labeling, identification, and Therapeutics, a biotech company that is developing a new class profiling. www.chemical-biology.org 43 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
A suite of Ac-CoA analogs containing either alkynyl or azido We have created a bioorthogonal, chemoproteomic strategy functional group (e.g. 3AZ-CoA, 4AZ-CoA, 4PY-CoA, 5HY-CoA, to investigate KAT biology which provides a powerful enabling 6HY-CoA) were synthesized as potential cofactor surrogate for technology for activity-based lysine acylation profiling on selective labeling of KAT substrates. Meanwhile, the active site proteomic scale. Our KAT activity profiling demonstrates of the KATs was engineered in order to expand the cofactor extensive engagement of KATs in cellular pathways and provides binding capability of the enzymes to accommodate the bulkier new molecular insights into understanding their functions in synthetic cofactors. Biochemical screening was conducted to biological processes. identify matching KAT-cofactor pairs to efficiently label protein and peptide substrates of KATs with alkyne or azide warhead. Abstract Author Biography We found out that several GCN5 mutant forms exhibited appreciable activities to the synthetic cofactors. MOF-I317A Y. George Zheng received his B.S. in chemistry at Peking was active toward all the Ac-CoA analogs. No mutation is University, Ph.D. at University of Miami, and postdoctoral training needed as the wild-type p300 exhibited robust activity to 4PY- at Johns Hopkins University School of Medicine. From 2006 to CoA and 3AZ-CoA. The acylated substrates can be selectively 2013, He was an Assistant Professor and Associate Professor linked through the copper-catalyzed azide-alkyne cycloaddition in the Department of Chemistry at Georgia State University. (CuAAC) reaction with fluorescent reporter or biotin affinity tag Since 2013, he has been an Associate Professor and Professor for optical imaging or protein enrichment on streptavidin-coated in the Department of Pharmaceutical & Biomedical Sciences resin. We have successfully used this bioorthogonal technology at University of Georgia. His research interest is on developing to profile substrates of p300 and GCN5 in the context of chemical probes and drug leads to target epigenetic enzymes. complex cellular proteomes.
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44 www.chemical-biology.org ICBS 2018
Biosensors and Imaging
A Suite of New Fluorescent Biosensors for New Colours and Applications of Dynamic Visualization of Cell Signaling in Genetically Encoded Biosensors to Probe Living Cells Cell Signaling
JIN ZHANG ROBERT CAMPBELL University of Alberta and The University University of California, San Diego of Tokyo San Diego, United States Edmonton, Canada
I will discuss development and application of a suite of new The advent of optogenetic tools, broadly defined here as both fluorescent biosensors for visualizing signaling activties in living actuators for cell control and indicators for cell visualization, cells. has revolutionized our ability to spy on the otherwise invisible world of neuronal activities. The most versatile class of Abstract Author Biography optogenetic indicators are the Ca2+ indicators that change their fluorescence intensity or color in response to intracellular Jin Zhang received her PhD in Chemistry from the U. Chicago. signaling events. These indicators are frequently used in After completing her postdoctoral work, she joined the faculty combination with optogenetic actuators to enable simultaneous of Johns Hopkins University School of Medicine in 2003. She control and visualization of cellular signalling with precise spatial was promoted to Professor of Pharmacology, Neuroscience and temporal resolution. However, a persistent challenge in and Oncology in 2013. In 2015 she moved to University this area is achieving sufficient spectral separation between of California, San Diego as a Professor of Pharmacology, the wavelengths of light required to excite the actuator and the Biochemistry and Bioengineering. Research in her lab focuses indicator. In this seminar I will describe our most recent efforts on developing enabling technologies to probe the active to use protein engineering to make highly red-shifted genetically molecules in their native environment and characterizing how encoded Ca2+ indicators that are suitable for use in combination these active molecules change in diseases including cancer. with blue-light activatable optogenetic actuators. In addition, I Professor Zhang is a recipient of the NIH Director’s Pioneer will discuss recent progress to develop new application of our Award (2009), the John J. Abel Award in Pharmacology from blue-light photocleavable optogenetic actuator, PhoCl. ASPET (2012), the Pfizer Award in Enzyme Chemistry from ACS (2012), and NCI Outstanding Investigator Award (2015). She Abstract Author Biography was elected as a Fellow of the AAAS in 2014. She serves on the editorial advisory board of Cell Chemical Biology and is the Dr. Robert E. Campbell is a Professor in the Department of Secretary/Treasurer of ASPET. Chemistry, University of Alberta (2003 - present). As of July 2018 he has a 50% appointment as Professor in the Department of Chemistry at the The University of Tokyo, and 50% appointment at the University of Alberta. He earned his Ph.D. in Chemistry with Martin Tanner at the University of British Columbia in 2000 and undertook postdoctoral research at the University of California San Diego in the lab of the late Roger Y. Tsien (2008 Nobel Prize). He is a leading developer of optogenetic tools, including red fluorescent Ca2+ indicators used in labs around the world. He has distributed >5000 samples of optogenetic tools through the Addgene plasmid repository and many others are distributed as viral vectors. Recent recognitions include a www.chemical-biology.org 45 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Stanford Neurosciences Institute Visiting Scholar Award (2017), Abstract Author Biography the Teva Canada Limited Biological and Medicinal Chemistry Award (2016), the Rutherford Memorial Medal from the Royal Dr. Ellen Sletten is an Assistant Professor in the Department Society of Canada (2015), and the Boehringer Ingelheim of Chemistry and Biochemistry at UCLA. She obtained her Research Excellence Award (2014). He has multiple patents B.S. in Chemistry from Stonehill College in 2006 and PhD awarded or pending. in Chemistry from UC Berkeley in 2011. Her thesis work was performed in Dr. Carolyn Bertozzi’s laboratory on the development of bioorthogonal chemistries. Upon graduation, Shortwave Infrared Fluorophores for Dr. Sletten moved to Massachusetts Institute of Technology Illuminating Biological Processes In Vivo as an NIH postdoctoral fellow in Dr. Timothy Swager’s group exploring dynamic fluorescence-based sensors. In 2015, Dr. Sletten began her independent career at UCLA, where she has established an interdisciplinary research program that leverages the tools of physical organic chemistry to create new optical ELLEN M. SLETTEN chemical tools and theranostic technologies. UCLA Los Angeles, United States Selectivity Differences Between Cellular and Biochemical Analysis
Chemical biologists have created a plethora of fluorescent probes that allow biological processes to be studied in real time. These methods have been exceedingly successful in cells and transparent organisms, but are less effective in higher mammals PONCHO MEISENHEIMER due to the limited penetration of light through tissue. Promega Biosciences San Luis Obispo, United States Recently, the shortwave infrared (SWIR) region of the electromagnetic spectrum has emerged as the premier region for optical imaging in mammals; however, there are limited fluorophores for use at SWIR wavelengths. Our group develops Quantitative assessment of kinase target occupancy in live cells, new fluorophores for the SWIR region of the electromagnetic under a thermodynamic equilibrium with the drug molecule, spectrum. We focus on polymethine dyes and modify the better reflects drug affinity under physiologically relevant local heterocycles to tune the absorption, emission, absorption ATP concentrations. Here we report the application of an coefficient, quantum yield, and solubility of the fluorophores. energy transfer technique (NanoBRET) that enables the first We have found that polymethine dyes with dimethylamino quantitative approach to profile target occupancy, compound flavylium heterocycles display significantly red-shifted affinity, and residence time for a broad spectrum of intracellular absorption and emission compared to traditional indolene- kinase enzymes. Using this technique, target occupancy data containing polymethine dyes (cyanine dyes). The dimethylamino correlates quantitatively with traditional intracellular activity/ flavylium heptamethine dye, deemed Flav7, emits at 1045 nm pathway analysis readouts. This method allows for broad- with quantum yield of ~ 0.6%, which is larger than commercially spectrum profiling of inhibitor selectivity against nearly 300 available SWIR polymethine fluorophores. We have prepared kinases, in a simple work-flow. We performed a systematic micelle formulations of Flav7 and obtained high-resolution comparison of kinase inhibitor selectivity in live cells versus optical images in mice. Additional work has surrounded biochemical analyses. Compared to published biochemical modification of the dimethylamino flavylium heterocycles profiling results, we observed an improved intracellular leading to enhanced photophysical properties and improved selectivity profile for certain clinically-relevant multi-kinase nanomaterial formulations. inhibitors. Moreover, this technique allowed for a mechanistic interrogation of micro-environmental ATP levels on engagement The SWIR region of the electromagnetic spectrum allows potency. When performed in real time, this technique enables for optical imaging in animals with superior resolution and/or a readout of compound residence time further supporting the depth penetration as compared to the visible and near infrared quantitative nature of this occupancy measurement. When regions. The development of polymethine fluorophores for the target engagement analysis is performed under equilibrium and SWIR region will facilitate the extension of optical chemical non-equilibrium conditions, surprising kinetic selectivity profiles biology tools to mammals. are observed for certain clinically-relevant kinase inhibitors.
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Abstract Author Biography DNA analysis, polymer development to enable capillary electrophoresis, and magnetic microparticle development to As Director of Chemistry Research for Promega, Poncho enable automated genomics. has long focused on live cell detection of the interactions He serves on the Scientific Advisory Board for the Usona Institute between endogenous and exogenous molecules. This group and for the Chemical Probes Portal, and has currently co- develops intracellular pro-luminescent probes for enzyme and authored over 30 journal articles/reviews and is an inventor for biomolecule detection, fluorescent tracers for energy transfer 29 issued patents and 81 pending patent applications. Poncho target engagement assays, novel fluorescent dye development, received his Ph.D. in Organic Synthesis at University of Colorado– novel bioluminescent substrates, and live cell selective protein Boulder and served on the faculty at California Polytechnic State labels. University–SLO prior to joining Promega Corporation in 2001. Additionally, Poncho has lead chemistry research programs in drug development to enable drug assisted psychotherapies, fluorescent amidite development to enable forensic
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www.chemical-biology.org 47 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada ICBS 2018
ICBS 2018 Rising Stars Sponsored by ACS Chemical Biology
Rising Stars To advance the career development of young investigators in increase O-GlcNAc levels in live cells. Fusion of the nanobody chemical biology, ICBS has established a special session at to full-length OGT(13), possessing 13 tetratricopeptide repeats the Annual Meeting to showcase up-and-coming chemical (TPRs), or a truncated OGT(4), possessing 4 TPRs, displayed biology scientists. The selected recipients will give a podium analogous glycosyltransferase activity in cells. Proximity-induced presentation during the special “Rising Stars” session, and glycosylation was demonstrated on ten nucleocytoplasmic each will be further recognized for their achievements with a proteins representing the broad array of substrates for OGT. certificate and a monetary award. Isotope targeted glycoproteomics (IsoTaG) was used to map specific glycosites yielded by proximity-induced glycosylation. Proximity-Directed O-GlcNAc Transferase In all evaluated target proteins, co-transfection with nanobody- OGT(13) or nanobody-OGT(4) increased O-GlcNAc stoichiometry for Protein-specific O-GlcNAcylation on the target protein. Evaluation of the effect of O-GlcNAc on some target proteins revealed altered subcellular localization. The changes in subcellular localization was attributed to increasing O-GlcNAc stoichiometry and scaffolding functions from OGT CHRISTINA WOO itself. Harvard University We report the ability to induce O-GlcNAc to specific proteins Cambridge, United States in live cells through introduction of an orthogonal, defined nanobody domain to OGT. The nanobody domain can replace part of the TPR domain, resulting in reduced innate substrate recognition through the TPR domain and generated more Over 15% of the cellular proteome is modified by O-linked N-acetyl selective constructs that increase O-GlcNAc levels on a range glucosamine (O-GlcNAc), a post-translational modification of nucleocytoplasmic proteins. Manipulation of O-GlcNAc that consists of a single glucosamine monosaccharide stoichiometry using proximity-directed OGT will catalyze attached to serine or threonine residues of nuclear, cytosolic additional discoveries of functions for O-GlcNAc and OGT itself. and mitochondrial proteins. Due to the ubiquitous nature of the modification, O-GlcNAc has been implicated in numerous Abstract Author Biography biological processes, including immune response, cancer progression, neurodegeneration, and diabetes. Despite a Christina M. Woo obtained a BA in Chemistry from Wellesley number of studies that point to the critical biological impact College (2008) and obtained her PhD in 2013 from Yale of O-GlcNAc on specific proteins, delineation of the function University under the guidance of Professor Seth B. Herzon. of O-GlcNAc modification on particular glycoproteins are In 2013, Christina joined the laboratory of Professor Carolyn hindered by the inability to control O-GlcNAc stoichiometry on R. Bertozzi at the University of California Berkeley as a Jane Coffins Child postdoctoral fellow and and Stanford University specific proteins of interest in cells. A general method to control as a Burroughs Wellcome Fund CASI Fellow. Christina joined glycosylation on specific target proteins would enable the the Department of Chemistry and Chemical Biology at Harvard systematic evaluation of O-GlcNAc function in cells. University as an Assistant Professor in 2016, where her group To advance insight into the role of O-GlcNAc on specific proteins, is studying chemoproteomic signaling using chemical biology we developed fusions of O-GlcNAc transferase (OGT) to and mass spectrometry methods to map and manipulate small nanobodies as proximity-directing agents to a target protein and molecule protein interactions.
48 ICBS 2018
ICBS 2018 Rising Stars Sponsored by ACS Chemical Biology
Chemoproteomics Profiling Reveals the assistant professor at Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University in Anti-Steatosis Mechanism of a Natural December, 2013 and is also affiliated with Synthetic and Functional Flavonoid Biomolecules Center (SFBC) and Peking-Tsinghua Center for Life Sciences (CLS) as a Principal Investigator. His current research programs focus on the development and application of multi- disciplinary tools in chemical proteomics, biochemistry and CHU WANG computational biology to streamline efforts in global profiling and College of Chemistry and Molecular discovery of functional sites, post-translational modifications and Engineering biomolecular interactions in proteomes. Peking University, China Decoding Protein Adp-Ribosylation Networks in Cells Using Chemical Genetic Hepatic steatosis, marked as excessive lipid accumulation in hepatocytes, constitutes the early stage of non-alcoholic fatty Approaches liver diseases (NAFLD), a world-wide epidemic that is strongly implicated with obesity and metabolic disorders. A natural flavonoid compound isolated from Chinese herbal medicine was shown with strong anti-steatosis effect, however, the MICHAEL COHEN mechanism of action remains elusive. Oregon Health and Science University, USA We employed a quantitative chemical proteomic strategy to deconvolute the protein targets of this compound. Photo- affinity probes were synthesized, SILAC-based chemical proteomics experiments were performed and multiple targets were identified. ADP-ribosylation (ADPr) is a reversibleposttranslational modification that is essential for cellular function, yet little Guided by functional pathway analysis, we discovered that information exists regarding relevant protein substrates and the flavonoid binds to a key enzyme in the fatty acid oxidation target specificity. ADPr is catalyzed by a family of 17 enzymes pathway and allosterically activates the enzyme to accelerates in humans known as poly-ADP-ribose-polymerases (PARP1-16 the rate of fatty acid degradation in the liver. Oral administration in humans; also known as ARTDs), which transfer the ADP- of the compound significantly ameliorates the symptoms ribose moiety from nicotinamide adenine dinucleotide (NAD+) associated with diet-induced obesity and hepatic steatosis. to amino acids on target proteins. The PARP family is sub- Our work revealed the mechanism of action of a natural flavonoid classified based on the ability of the individual PARP enzymes to compound with unique anti-steatosis activity and suggested catalyze the transfer of a single ADP-ribose unit (mono-PARPs: that flavonoids may serve as a common scaffold to develop PARP3, 6-8, 10-12, 14-16) or multiple ADP-ribose units (poly- novel drugs for pharmacological treatment of NAFLD. PARPs: PARP1-2, 4, 5a, 5b) onto target proteins. Progress in understanding the specific role of a given PARP in cells has Abstract Author Biography been severely limited by the inability to identify the direct targets for individual PARPs in a cellular context. Dr. Chu Wang obtained his B.S. degree in Biology from University To address this challenge, my laboratory has designed novel of Science and Technology of China (USTC) in 2001 and his orthogonal NAD+analog-engineered PARP pairs for the Ph.D. degree with Professor David Baker in 2007 from University identification of direct protein targets of individual PARPs. The of Washington. He did his postdoctoral training with Professor orthogonal NAD+ analog contains a benzyl group at the C-5 Benjamin F. Cravatt at The Scripps Research Institute from position of the nicotinamide ring, which interacts with a hydrophobic 2009 to 2013 and was supported by NIH / NIEHS Pathways to pocket uniquely found in the engineered PARPs, and an alkyne Independence (K99/R00) postdoctoral award. He started as an tag at the N-6 position on the adenosine ring for copper-catalyzed
49 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
ICBS 2018 Rising Stars Sponsored by ACS Chemical Biology conjugation to a biotin−azide probe. We have successfully applied Abstract Author Biography our chemical genetic approach toward the identification of the direct targets of the poly-PARP subfamily, and have recently Michael Cohen received his B.S. in Chemistry from University extended this strategy to the mono-PARP subfamily. of California, Irvine. His interest in the chemistry and biology interface led him to pursue a Ph.D. in Chemistry and Chemical I will discuss our unpublished work on identifying the direct Biology at the University of California, San Francisco under targets of the mono-PARP, PARP14. PARP14 is involved in the supervision of Jack Taunton. In his graduate studies, he normal immune function through the IL-4 signaling pathway and developed structural bioinformatics-based approaches for is a pro-survival factor in multiple myeloma and hepatocellular generating selective protein kinase inhibitors. He then pursued carcinoma. Combining our chemical genetics approach postdoctoral studies with Samie Jaffrey at Cornell Medical with a BioID approach for proximity-dependent labeling of College where he investigated compartmentalized NAD+ PARP14 interactors, we identified 114 PARP14-specific protein biosynthesis. In 2011, he began his independent career at substrates, several of which are RNA regulatory proteins. One Oregon Health and Science University where his lab is focused of these targets is PARP13, a protein known to play a role in on using chemistry-based approaches to investigate NAD+ regulating RNA stability. PARP14 MARylates PARP13 on several signaling. His lab is particularly interested in enzymes known acidic amino acids. as PARPs, which are the major consumers of NAD+ in the cell This study not only reveals crosstalk among PARP family and mediate post-translational modification known as ADP- members but also highlights the advantage of using disparate ribosylation. Over the last several years, his lab has developed approaches for identifying the direct targets of individual PARP novel chemical tools which have revealed new roles for PARPs family members. and ADP-ribosylation in cells.
Past Rising Stars
2017 2015 2013
Toru Komatsu Alessio Ciulli Bradley L. Pentelute, University of Tokyo University of Dundee, UK Massachusetts Institute of Technology Qi Zhang Edward Lemke Christian Ottmann, Fudan University EMBL, Germany Eindhoven University of Technology, Haitao Zhang Evan Miller Netherlands Zhejiang University University of California Berkley Xiaoguang Lei,
National Institute of Biological Sciences, China 2016 2014
Yimon Aye Evripidis Gavathiotis Cornell University Albert Einstein College of Medicine Ratmir Dedra Kenjiro Hanaoka University of Alberta University of Tokyo William Pomerantz Jiaoyang Jiang University of Minnesota University of Wisconsin-Madison
50 Fully Integrated Contract Research and Manufacturing Platform for Life Sciences and Industries
HTS Compounds Custom Synthesis Building Blocks Computational Chemistry Fragment Libraries Early Drug Discovery Targeted and Focused Libraries Primary Drug Trial Services
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52 www.biotek.com www.chemical-biology.org ICBS 2018
Poster Presenters
Board Presenter Poster Title Category Number DIRECT FLUORESCENT LABELING OF O-GLCNAC MODIFIED PROTEINS IN LIVE CELLS Hong Yee Tan P-02 Glycobiology USING METABOLIC INTERMEDIATES AS PRECURSORS A NOVEL MECHANISM BASED APPROACH FOR SCREENING METAGENOMIC LIBRARIES Seyed Nasseri P-03 Glycobiology FOR UNUSAUL GLYCOSIDASES DEVELOPMENT OF A SERIES OF FLUORESCENCE PROBES TO MEASURE PH VALUES Kenjiro Hanaoka P-04 Imaging Tools IN LIVING SAMPLES DEVELOPMENT OF AN ACTIVATABLE PHOTOACOUSTIC PROBE FOR HYPOCHLOROUS Takayuki Ikeno P-05 Imaging Tools ACID INNOVATIVE APPROACHES FOR SECURE, MODERN COLLABORATIVE DRUG Heather Arnaiz P-07 Medicinal Chemistry DISCOVERY James Meinig TARGETED PRODRUGS FOR CNS-SELECTIVE DRUG DISTRIBUTION P-08 Medicinal Chemistry ALBUMIN-BINDING PENTAFLUOROPHENYL-SULFIDE PEPTIDE MACROCYCLE WITH Jeffrey Y.K. Wong P-09 Medicinal Chemistry EXTENDED CIRCULATION HALF-LIFE IN VIVO EXPLOITING CHEMICAL SYNTHETIC-LETHAL INTERACTIONS TO TARGET Dennis Liu P-10 Natural Products Chemistry ANTIMICROBIAL-RESISTANT PATHOGENS A SELECTIVE GENOME-GUIDED METHOD FOR ENVIRONMENTAL BURKHOLDERIA Fred Haeckl P-11 Natural Products Chemistry ISOLATION Joseph Egan USING NMR TO UNLOCK CHEMICAL DIVERSITY FROM NATURAL PRODUCT EXTRACTS P-12 Natural Products Chemistry NATURAL PRODUCTS LIBRARY DIVERSIFICATION THROUGH CHEMICAL Nicole LeGrow P-13 Natural Products Chemistry TRANSFORMATION DEVELOPMENT OF A CHEMICAL BIOLOGY SCREEN FOR INHIBITORS OF STOP-GO Jasmine Li-Brubacher P-14 Other TRANSLATION IDENTIFICATION OF CYTOTOXIC, GLUTATHIONE-REACTIVE MOIETIES INDUCING Julian Wilke P-15 Other ACCUMULATION OF REACTIVE OXYGEN SPECIES VIA GLUTATHIONE DEPLETION Karson Kump TARGETING MCL-1 TO OVERCOME RESISTANCE IN SOLID TUMORS P-16 Other Thomas Garner ALLOSTERIC MODULATION AND THERAPEUTIC INHIBITION OF PRO-APOPTOTIC BAX. P-17 Other IN PURSUIT OF SMALL MOLECULE INHIBITORS OF ETV6 PNT DOMAIN Chloe Gerak P-19 Protein-Protein Interactions POLYMERIZATION PHOTOACTIVATABLE FARNESYL-ANALOGUES AS PROBES TO IDENTIFY PROTEIN- Michael Winzker P-20 Protein-Protein Interactions PROTEIN INTERACTIONS Alena Istrate CYCLOPROPENONE REAGENTS FOR SITE-SELECTIVE CYSTEINE BIOCONJUGATION P-21 Synthetic Biology Kenzo Yamatsugu SYNTHETIC HISTONE ACYLATION WITH CHEMICAL CATALYSTS P-22 Synthetic Biology IN SEARCH FOR AN AFKDNASE INHIBITOR: A POTENTIAL THERAPEUTIC FOR TREATING Ali Nejatie P-23 Synthetic Chemistry INVASIVE ASPERGILLOSIS Barbara Sohr CHEMICAL PROBES FOR INTRACELLULAR HYPOXIA TARGETING P-24 Synthetic Chemistry PROGRAMMABLE CHEMICAL ASSEMBLY OF NON-NATURAL AMINO ACIDS USING DNA- Charlotte Zammit P-25 Synthetic Chemistry TEMPLATED ORGANIC SYNTHESIS Nicole Houszka INTRACELLULAR BIOORTHOGONAL CLEAVAGE P-26 Synthetic Chemistry DEVELOPMENT OF SMALL MOLECULE COMPOUNDS FOR TREATMENT OF PATIENTS Target Engagement/ Saiko Shibata P-27 WITH CYSTIC FIBROSIS CARRYING THE SPLICING MUTATION Mechansims DIFFERENTIAL REGULATION OF PRO-INFLAMMATORY CYTOKINE SECRETION VIA SMALL Target Engagement/ Wansang Cho P-28 MOLECULE TARGETING RECYCLING ENDOSOMAL PROTEIN RAB11 Mechansims A NOVEL SCENARIO OF BACTERIAL INFECTION IN PLANT: CORONATINE INDUCES Syusuke Egoshi P-31 Natural Products Chemistry STOMATAL OPENING THROUGH TWO DIFFERENT TARGET PROTEINS IN GUARD CELLS CUTTING THE GLUCOSE SUPPLY OF CANCER CELLS BY MEANS OF SMALL Target Engagement/ Elena Reckzeh P-32 MOLECULES Mechansims NEW PALLADIUM CATALYSTS FOR IN CELLULO PROBE UNCAGING: FROM THE BENCH Mathieu Soetens P-33 Imaging Tools TO CELLS
www.chemical-biology.org 53 7th Annual Conference | September 24-27, 2018 | Vancouver, Canada
Board Presenter Poster Title Category Number SELECTIVE PURIFICATION AND LABELING OF LIGAND-BINDING PROTEINS ON Michihiko Tsushima P-35 Other RUTHENIUM PHOTOCATALYST FUNCTIONALIZED AFFINITY BEADS A CLICK PROBE-BASED APPROACH FOR VISUALIZATION OF DRUG-TARGET Target Engagement/ Anna Rutkowska-Klute P-36 INTERACTIONS AND TARGET ENGAGEMENT MEASUREMENT AT SINGLE CELL LEVEL Mechansims AFFINITY CONTROLLED INDUCTION OF ANTIBODY-DEPENDENT CELL-MEDIATED Koichi Sasaki P-37 Medicinal Chemistry CYTOTOXICITY BY FC BINDING ANTIBODY RECRUITING MOLECULES Guillaume Médard CHEMOPROTEOMICS-AIDED DRUG DISCOVERY P-38 Medicinal Chemistry Polina Prokofeva PROTEOME-WIDE STRUCTURE-AFFINITY RELATIONSHIPS P-40 Medicinal Chemistry 50 SHADES OF KINASE INHIBITION – APPLICATIONS OF THE TARGET LANDSCAPE OF Target Engagement/ Stephanie Heinzlmeir P-41 CLINICAL KINASE DRUGS Mechansims DEVELOPMENT OF EP2 ANTAGONISTS: FROM ASSAY DEVELOPMENT TO PRECLINICAL Thota Ganesh P-42 Medicinal Chemistry LEAD OPTIMIZATION. NITRIC OXIDE DONATING RUTHENIUM(II) COMPLEXES AS ANTICANCER AND Shireen Jozi P-43 Medicinal Chemistry ANTIBACTERIAL AGENTS CHEMICAL PROBE DISCOVERY TO INTERROGATE YAP-TEAD INTERACTION IN THE Kun Qian P-45 Protein-Protein Interactions HIPPO SIGNALING PATHWAY Phillip Danby GLYCOSIDE HYDROLASE CATALYZED HYDROLYSIS OF NON-GLYCOSIDIC LINKAGES P-48 Glycobiology ANTIMYCOBACTERIAL AND CYTOTOXICITY STUDIES ON CINNAMIC ACID DERIVATIVE Victor Fadipe P-54 Medicinal Chemistry OF OLEANOLIC ACID AT C-28 POSITION Amy Weeks MAPPING PROTEOLYSIS AT THE SURFACE OF LIVING CELLS P-55 Degradomics Eline Sijbesma DISULFIDE TRAPPING FOR THE DISCOVERY OF SELECTIVE PPI MODULATORS P-56 Protein-Protein Interactions Masayasu Toyomoto DRUG DISCOVERY BY RE-SEARCHING CANCER METABOLISM AND GPCR SIGNALING P-58 Other Matthew Alteen CHEMICAL TOOLS FOR THE DISCOVERY OF O-GLCNAC TRANSFERASE INHIBITORS P-62 Glycobiology INFLUENCE OF NON-NATURAL AMINO ACIDS ON THE BIOLOGICAL ACTIVITY PROFILE Evan Haney P-63 Medicinal Chemistry OF SYNTHETIC HOST DEFENCE PEPTIDES Sebastian Andrei PRINCIPLES BEHIND THE STABILIZATION OF PROTEIN-PROTEIN INTERACTIONS P-64 Medicinal Chemistry IN VITRO CHARACTERIZATION OF A CRYPTIC GENE CLUSTER ENCODING AN O2, PLP- Jason Hedges P-65 Natural Products Chemistry DEPENDENT OXIDASE Cameron Murray FINDING INHIBITORS OF PNKP TO TREAT PTEN DEFICIENT CANCERS P-67 Medicinal Chemistry LONG CIRCULATING SINGLE POLYMER NANOPARTICLES FORM A DYNAMIC PROTEIN Lily Takeuchi P-69 Other CORONA IN VIVO UNPRECEDENTED TAMBJAMINE ALKALOIDS DETECTED IN THE EXTRACT OF THE Mirelle Takaki P-70 Natural Products Chemistry MANTLE OF THE NUDIBRANCH ROBOASTRA ERNSTI A MULTIPLEXED QUANTITATIVE TARGET ENGAGEMENT TECHNOLOGY TO DISCOVER AND VALIDATE THE MECHANISM OF BROAD-SPECTRUM ANTIPROTEOLYTIC Target Engagement/ Francois Jean DRUG CANDIDATES: N-TERMINAL ACETYL (NTAC)-MRM ASSAYS TO QUANTIFY P-72 Mechansims HOST-MEDIATED ENDOPROTEOLYTIC CLEAVAGE OF ENVELOPE GLYCOPROTEIN PRECURSORS OF PATHOGENIC VIRUSES. Akane Kawamura CYCLIC PEPTIDE TOOLS FOR EPIGENETIC PROTEINS P-73 Protein-Protein Interactions TARGETED NUDT5 INHIBITORS BLOCK HORMONE SIGNALING IN BREAST Brent Page P-74 Medicinal Chemistry CANCER CELLS Doug Auld INTRODUCTION TO THE FAST-LAB: NOVARTIS OPEN SPACE FOR COLLABORATIONS P-75 Other
54 www.chemical-biology.org Downtown Vancouver
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Y S www.chemical-biology.org 55 T 7th Annual Conference September 24-27, 2018 ICBS 2018 Vancouver, Canada
www.chemical-biology.org