The 9th Annual Conference of the International Chemical Biology Society

ICBS2020VIRTUAL

Addressing Therapeutic Challenges Together with Chemical Biology

November 11, 2020 7:30 PM to 11:30 PM EST November 12, 2020 9:30 AM to 2:00 PM EST November 13, 2020 9:30 AM to 2:40 PM EST 9th Annual Conference | November 11-13, 2020 | Virtual

Table of Contents Table of Contents...... 1 Session 3: Academic-Industry Partnerships Acknowledgements...... 1 case studies...... 23 ICBS Board of Directors...... 2 Session 4: Chemical Biology of Small Molecule About ICBS...... 2 Protein Degraders...... 28 ICBS International Advisory Board...... 3 EFMC Speaker...... 32 ICBS Global Council...... 4 Session 5: Chemical Technologies to Promote Welcome Letter...... 5 Drug Discovery...... 33 Trainee Pre-Conference Program...... 6 Rising Stars Session...... 37 Detailed Program...... 7 Opening Day Trainee Forum...... 41 Session 1: In-Cell Chemistry...... 16 Presenter Index...... 51 Session 2: COVID-19, Disease Modeling, and Thank you to our conference sponsors...... 52 Drug Discovery...... 19

Acknowledgements ICBS2020 Virtual Host Biological Discovery through Chemical Innovation Initiative (BDCI), Emory University

ICBS2020 Program Committee Huw Davies (co-chair), Haian Fu (co-chair), Douglas Auld, Jonathan Baell, Shuibing Chen, Jen Heemstra, Zaneta Nikolovska-Coleska, Tom Pfeifer

ICBS2020 Local Organizing Committee Dennis Liotta, Jae Won Chang, Yuhong Du, M.G. Finn, Jen Heemstra, Shafiq Khan, Kojo Mensa-Wilmot, Eddie Morgan, Binghe Wang, Daqing Wu, Bill Wuest, Y. George Zheng

ICBS2020 Virtual Operations Team Tiffany R. Bell-Horwath, Andrey A. Ivanov, Rachel Commander, Kun Qian, Rio Febrian

ICBS2020 Trainee Forum Organizing Committee Kun Qian, Danielle Cicka, Amber Scharnow, Andre Mahoney, Ashley Modell, Jana Flegel, Jessica Nowacki, Aylin Binici, Kirujan Jeyakumar, Yuting Shuai

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ICBS Board of Directors

Douglas S. Auld Jonathan Baell Rathnam Chaguturu (USA) President (Aus) Treasurer (USA)

Haian Fu Zaneta Nikolovska-Coleska Hiroyuki Osada Chair of Board (USA) President-Elect (USA) (Japan)

Tom Pfeifer Siddhartha Roy Lixin Zhang Secretary (Can) (India) Past President (China) 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, nonprofit 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 Chris Lipinski Penn State University of Dundee Shanghai Institute of Melior Discovery Materia Medica

Ferid Murad Bernard Munos Litao Zhang Stuart Schreiber George Washington InnoThink Bristol-Myers Squibb Harvard University

Paul Workman Tetsuo Nagano Leonard Zon Herbert Waldmann ICR-London University of Tokyo HHMI/Harvard Max Planck Institute of Molecular Physiology

Junying Yuan Harvard

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ICBS Global Council

Seung Bum Park William Pomerantz Xiaoguang Lei Sally-Ann Poulsen Mahabir Gupta Bridget Wagner Chair Co-Chair

Mikiko Sodeoka Jiaoyang Jiang Ratmir Derda Changlin Tian Jason Micklefield

Hanne Ingmer Christian Richard Pyane Kamyar Hadian Shi Chen Ottmann

Haitao Zhang Eliezer J. Barreiro Qi Zhang Toru Kamatsu Evripidis Gavathiotis

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Welcome Letter Dear ICBS2020 Participants:

On behalf of the ICBS leadership and the host organization, we would like to welcome each of you to this global virtual event, the 9th Annual Conference of the International Chemical Biology Society!

It is an extraordinary time in the midst of the COVID-19 pandemic, which has impacted the lives of people across the world and led to major social and economic disruptions. We strongly believe that the chemical biology community can play important roles in addressing the challenges of today and beyond. Although we are unable to meet in person as we originally planned, we are excited to utilize the virtual platform to highlight the power of chemical biology to bring the community together to exchange ideas, present discoveries, and discuss emerging concepts to advance science. In particular, our program is organized to showcase the impact of collaborations and partnerships on driving chemical biology research to accelerate therapeutic discovery. We appreciate the enthusiastic participation of the thought leaders in the field as keynote speakers as they share their perspectives and inspire others. We hope that you will enjoy the presentations, thoughtfully put together by session chairs, that describe cutting edge chemical technologies and mechanistic interrogation strategies for disease biology insights.

During the Opening Day Trainee Forum, which is organized by ICBS Student Chapters, ICBS2020 will feature discoveries by students and postdocs and a career discussion session to advance the professional development of trainees. We hope you will show your support and join this forum. We will also continue our tradition of showcasing emerging leaders of the field with the Rising Stars Special Session. Four outstanding ICBS Young Chemical Biologist awardees have been selected from a record number of incredible nominees. Let us come together to congratulate the rising stars of chemical biology.

We would like to thank each of you, ICBS2020 participants, for your heartening response to this virtual conference. As of the day prior to ICBS2020 opening day, the number of registered participants from around the world has surpassed 1,500, representing over 50 countries and more than 300 cities. Your participation will define the success of this conference. We encourage you to engage in discussions and use the Chat and Q&A channels as well as the networking sessions to communicate with each other and the speakers.

Join, connect, and inspire as a collaborative community to advance chemical biology and to address therapeutic challenges together!

Enjoy the ICBS2020 Virtual Conference.

Sincerely,

Huw Davies, Ph.D. Professor of Chemistry, Emory University Haian Fu, Ph.D. Professor of Pharmacology & Chemical Biology, Emory University Co-Chairs, ICBS2020

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10:00 AM to 1:00 pm, November 11, 2020 (EST)

Trainee Pre-Conference Program The ICBS2020 trainee forum features presentations from students and postdocs in the field of chemical biology as well as a career talk and panel discussion session with academic and industry experts! The forum aims to unite young researchers from the ICBS network, facilitate communication of new research, improve collaborative endeavors, and provide educational opportunities to the trainees in the field of chemical biology.

10:00 AM - 10:05 AM Welcome & Opening by the Trainee Forum Organizing Committee 10:05 AM - 10:55 AM Trainee Presentations Session A 10:05 AM - 10:17 AM Maria L. Adrover-Castellano, University of Michigan “Thioesterase directed evolution approach for yield improvement and expansion of the substrate scope to generate macrolactones” 10:17 AM - 10:30 AM Jiang Lan, East China University of Science and Technology “Fungal multi-functional cytochrome-P450 responsible for the biosynthesis of unprecedented BFTS-related norditerpenoids” 10:30 AM - 10:42 AM Hyungyu Lee, Emory University “Comparison of covalent delivery methods and their effects for immune-mediated killing of Helicobacter pylori” 10:42 AM - 10:55 AM Beverly Y. Mok, Broad Institute of MIT and Harvard “A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing” 11:00 AM - 11:55 PM Career Talk and Panel Discussion Dr. Colleen Keohane, Scientist, Discovery Chemistry, Janssen Dr. Luca Laraia, Assistant professor, Technical University of Denmark Dr. Kathryn Hosbein, Postdoctoral Associate & Chemistry Education Researcher, University of Michigan 12:00 PM - 1:00 PM Trainee Presentations Session B 12:00 PM - 12:12 PM Pragya Jatoo, Lead Discovery Center GmBH (LDC) “A Chemical Biology approach to decipher the Tubulin Code” 12:12 PM - 12:24 PM Dacheng Fan, University of Wisconsin-Madison “Targeted covalent inhibition of O-GlcNAc transferase in cells” 12:24 PM - 12:36 PM Shwetha Srinivasan, Massachusetts Institute of Technology “Conformational coupling across the membrane bilayer of epidermal growth factor receptor” 12:36 PM - 12:48 PM Elisabeth Hennes, Max Planck Institute of Molecular Physiology “Detection of modulators of the kynurenine pathway in cells” 12:48 PM - 1:00 PM Dhanushka N. P. Munkanatta Godage, Broad Institute of MIT and Harvard “Phosphorylation-inducing chimeric small molecules”

Presentation Awards Sponsored by

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10:00 AM to 1:00 pm, November 11, 2020 (EST) 7:30 PM to 11:30 PM, November 11, 2020 (EST)

Detailed Program 7:30 PM - 7:50 PM Virtual Event Open, with conference and session information 7:50 PM - 8:00 PM Opening Remarks by ICBS President, Jonathan Baell, Monash University 8:00 PM - 8:30 PM Keynote Speaker Dr. Zijian Guo, Nanjing University “Chemical Biology of Platinum-based Anticancer Agents” Moderated by: Dr. Bridget Wagner, Broad Institute of MIT and Harvard University 8:30 PM - 9:30 PM Session 1: In-Cell Chemistry (Co-Chairs: Gonçalo Bernardes, University of Cambridge & Keriann Backus, UCLA) 8:30 PM - 8:50 PM Keriann Backus, University of California, Los Angeles “Expanding the activity-based chemoproteomic toolbox” 8:50 PM - 9:10 PM Gonçalo Bernardes, University of Cambridge, UK & Instituto de Medicina Molecular, Lisbon, Portugal “A small-molecule targeted RNA degradation approach” 9:10 PM - 9:30 PM Justin Chalker, Flinders University, Adelaide, Australia “The chemical biology of cysteine oxidation” 9:30 PM - 10:30 PM Session 2: COVID-19, Disease Modeling, and Drug Discovery (Chair: Shuibing Chen, Cornell University)

9:30 PM - 9:45 PM Shuibing Chen, Weill Cornell Medicine “Repurposing FDA-Approved Drugs for COVID-19”

9:45 PM - 10:00 PM Nigel Greig, National Institute on Aging “Developing agents to mitigate the systemic and neurological inflammatory component of COVID-19” 10:00 PM - 10:15 PM Gabsang Lee, Johns Hopkins University SOM “Optogenetic alpha-synuclein aggregation system-based compound screening platform in PD hiPSC-derived mDA neurons” 10:15 PM - 10:30 PM Zhexing Wen, Emory University SOM “Modeling viral infection and screening therapeutic compounds with human iPSC-derived neural cells and brain organoids” 10:30 PM - 11:00 PM Keynote Speaker Dr. Mikiko Sodeoka, RIKEN, Japan “Potential of Raman Spectroscopy in Chemical Biology Research” Moderated by: Dr. William Pomerantz, University of Minnesota 11:00 PM - 11:30 PM Virtual Event Open for social networking and discussion

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9:30 AM to 2:40 PM, November 12, 2020 (EST) 9:30 AM to 2:00 PM, November 13, 2020 (EST)

Detailed Program 9:30 AM - 10:00 AM Virtual Event Open, with conference and session information 10:00 AM - 10:30 AM Keynote Speaker Dr. James (Jay) Bradner Novartis “Chemical Biology & Therapeutics” Moderated by: Dr. Douglas S. Auld, Novartis Institutes for Biomedical Research 10:30 AM - 11:30 AM Session 3: Academic-Industry Partnerships case studies (Co-Chairs: Doug Auld, Novartis & Sherry Niessen, Pfizer) 10:30 AM - 10:45 AM Tim Willson, University of North Carolina and Matthew Robers, Promega “NanoBRET Target Engagement to Illuminate the Dark Kinome” 10:45 AM - 11:00 AM Manuel de Lera Ruiz, Merck “Targeting Essential Plasmepsin Proteases – An Efficient Academic/Industrial Collaboration toward the Next Generation of Antimalarial Agents” 11:00 AM - 11:15 AM Douglas S. Auld, Novartis Institutes for Biomedical Research “Novartis FAST Lab: Fostering Innovation in chemical biology through academic collaborations” 11:15 AM - 11:30 AM Daniel K. Nomura, University of California, Berkeley “Reimagining Druggability using Chemoproteomic Platforms” 11:30 AM - 11:40 AM Break 11:40 AM - 12:40 PM Session 4: Chemical Biology of Small Molecule Protein Degraders (Chair: Andrew Zhang, AstraZeneca) 11:40 AM - 11:55 AM Andrew Zhang, AstraZeneca “Introduction: Targeted Protein Degradation at AstraZeneca” 11:55 AM - 12:10 PM Adam Gilbert, Pfizer “BTK Protein Degradation: Delineating the Role of Cooperativity in the Design of Potent PROTACs” 12:10 PM - 12:25 PM Danette Daniels, Promega Corporation “Cellular Mechanistic Profiling of Degradation Compounds” 12:25 PM - 12:40 PM Georg Winter, CeMM-Center for Molecular Medicine of the Austrian Academy of Science “Discovery and Characterization of Novel Molecular Glue Degraders” 12:40 PM - 1:10 PM EFMC Lecture Nir London, Weizmann Institute of Science, Israel “From covalent inhibitors to covalent PROTACs” Moderated by: Dr. Yves Auberson, European Federation of Medicinal Chemistry 1:10 PM - 1:40 PM Keynote Speaker Dr. Alanna Schepartz, University of California, Berkeley “Novel molecules from a repurposed translation machine” Moderated by: Dr. Jiaoyang Jiang, University of Wisconsin-Madison 1:40 PM - 2:10 PM RSC Chemical Biology: Meet the Editors - Introducing a New Journal

2:10 PM - 2:40 PM Virtual Event Open for social networking and discussion

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9:30 AM to 2:00 PM, November 13, 2020 (EST)

Detailed Program 9:30 AM - 10:00 AM Virtual Event Open and ICBS business meeting 10:00 AM - 10:30 AM Keynote Speaker Dr. Stuart Schreiber, Harvard University and Broad Institute “30 years of Molecular Glues: Controlling cell circuitry in biology and medicine” Moderated by: Dr. Seung Bum Park, Seoul National University 10:30 AM - 11:30 AM Session 5: Chemical technologies to promote drug discovery (Co-Chairs: Huw Davies & Monika Raj, Emory University) 10:30 AM - 10:40 AM Hans Renata, The Scripps Research Institute “A Chemoenzymatic Platform for the Production of Covalent Inhibitor Natural Products and Analogs Thereof” 10:40 AM - 10:50 AM Monika Raj, Emory University “Chemical Tools for Selective Detection of Monomethyl Lysine PTMs” 10:50 AM - 11:10 AM Rob Oslund, Merck Exploratory Science Center “Mapping Immune Cell Interactions via Photocatalytic Proximity Labeling” 11:10 AM - 11:30 AM Phil Baran, The Scripps Research Institute “Simplicity and Ideality in Synthesis” 11:30 AM - 11:40 AM Break 11:40 AM - 12:40 PM Rising Stars Session: ICBS2020 Young Chemical Biologist Award Lectures (Chair: Haian Fu, Emory University) 11:40 AM - 11:55 AM Ellen Sletten, University of California, Los Angeles “Multicolor, high resolution, non-invasive imaging in mice” 11:55 AM - 12:10 PM Jordan L. Meier, National Cancer Institute, USA “New insights into acetylation & oncometabolism from chemoproteomics” 12:10 PM - 12:25 PM Amit Choudhary, Harvard Medical School “Precision control of CRISPR-associated nucleases” 12:25 PM - 12:40 PM Gonçalo Bernardes, University of Cambridge & Instituto de Medicina Molecular “Translational Site-Selective Antibody Modification” 12:40 PM - 1:10 PM Keynote Speaker Dr. Herbert Waldmann, Max Planck “Pseudo Natural Products – Chemical Evolution of Natural Product Structure” Moderated by: Dr. Zaneta Nikolovska-Coleska, University of Michigan 1:10 PM - 1:20 PM Concluding Remarks by ICBS President-Elect Zaneta Nikolovska-Coleska, University of Michigan 1:20 PM - 2:00 PM Virtual Event Open for social networking and discussion

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Keynote Speaker Dr. Zijian Guo Prof. Guo received his PhD degree from the University of Padova and worked as a postdoctoral research fellow at Birkbeck College, the University of London. He worked also as a research associate at the University of Edinburgh. He joined the School of Chemistry and Chemical Engineering at Nanjing University as a professor of chemistry in 1999. He has co-authored over 200 publications since established his independent group. He was awarded the First Prize in Natural Sciences from Ministry of Education of China in 2015, and received the Luigi Sacconi Medal from the Italian Chemical Society in 2016. He was elected to the fellow of the Chinese Academy of Sciences in 2017. The research interest of his Cheung Kong professor of lab focuses on the chemical biology of metals and metallodrugs. Chemistry and Chemical Engineering, Nanjing University, China “Chemical Biology of Platinum-based Anticancer Agents” Platinum-based anticancer drugs play an important role in the treatment of various malignancies such as colorectal and testicular cancers. However, drug resistance and side effects are challenging problems that hinder their wider clinical applications. Chemical biology approaches could be applied for elucidating the mechanism of action of different platinum anticancer drugs, and provides important tools for understanding the biological effects of platinum anticancer complexes in cellular energy conversion, metabolism and apoptosis.

In this lecture, I will focus on the molecular design of platinum-based antitumor complexes with multi-specific targeting potentials. These results demonstrated that in addition to DNA binding, bio-energetic pathways may also play crucial roles in the antitumor activity of mitochondrion-targeted platinum complexes. The combination of chemotherapy and immunotherapy in one molecule offers potential superiority for the treatment of triple negative breast cancer. A label-free comparative proteomic study was performed to profile the protein post-translational modifications using Pt-DNA probes was also developed.

1. “Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX-2 and PD-L1”, Jin, S.X., Muhammad, N., Sun, Y.W., Tan, Y.H., Yuan, H., Song, D.F., Guo, Z.J.*, Wang, X.Y.* Angew. Chem. Int. Ed., 2020, doi.org/10.1002/ange.202011273. 2. “A Potential Therapeutic Agent for Acute Promyelocytic Leukaemia Cells by Acting on Nuclear Proteins”, Wang, X.X., Hu, Y., Mo, J.B., Zhang, J.Y., Wang, Z.Z., Wei, W., Li, H.L., Xu, Y., Ma, J., Zhao, J.,* Jin, J.*, Guo, Z.J* Angew. Chem. Int. Ed., 2020, 5189-5196. 3. “Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(IV) prodrugs”, Zhang, S.R. Zhong, X.M., Yuan, H., Guo, Y., Song, D.F., Qi, F., Zhu, Z.Z., Wang, X.Y.*, Guo, Z.J.* Chem. Sci., 2020, 11, 3829-3835. 4. “Restraining Cancer Cells by Dual Metabolic Inhibition with a Mitochondrion-Targeted Platinum(II) Complex”, Wang K., Zhu, C.C., He, Y.F., Zhang, Z.Q., Zhou, W., Muhammad, N., Guo, Y., Wang, X.Y., Guo, Z.J.* Angew. Chem., Int. Ed., 2019, 58, 4638-4643. 5. “Photoactivated Lysosomal Escape of a Monofunctional Pt(II) Complex Pt-BDPA for Nucleus Access”, Xue, X.L., Qian, C.G., Fang, H.B., Liu, H.K., Yuan, H., Guo, Z.J.*, Bai, Y., He, W.J.* Angew. Chem. Int. Ed., 2019, 58, 12661-12665. 6. “Stimuli-Responsive Therapeutic Metallodrugs”, Wang, X.H. Wang, X.Y.*, Jin, S.X., Muhammad, N., Guo, Z.J.,*Chem. Rev., 2019, 119, 1138-1192.

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Keynote Speaker Dr. Mikiko Sodeoka Mikiko Sodeoka received her Master’s degree from Chiba University (1983). She then worked with Prof. Masakatsu Shibasaki at Sagami Chemical Research Center and at Hokkaido University and received her PhD degree in 1989. After working at Harvard University with Prof. E. J. Corey and Prof. Gregory L. Verdine (1990- 1992), she moved to the University of Tokyo. She started her independent career at Sagami Chemical Research Center in 1996, and became an associate professor of the University of Tokyo in 1999. In 2000 she moved to Tohoku University as a full professor. Since 2006 she has been a Chief Scientist at RIKEN. She has received many awards including the Encouraging Award of the Pharmaceutical Society of Japan (1993), The Chemical Society of Japan Award for Creative Work Chief Scientist, RIKEN Cluster (2004), Nagoya Medal (Silver) (2007), Synthetic Organic Chemistry Award, for Pioneering Research, RIKEN, Japan (2016), and Arthur C. Cope Scholar Award (2017). Japan

“Potential of Raman Spectroscopy in Chemical Biology Research” Raman spectroscopy is a powerful tool to analyze structures of molecules. Recent advances in Raman microscopy have opened up the possibility of its application to life science research. We intended to use Raman spectroscopy in chemical biology research, and focused on the fact that biorthogonal alkyne shows unique Raman signal that does not overlap with major Raman scattering from endogenous molecule in live cells, such as proteins and lipids. We have successfully demonstrated that alkyne-tag Raman imaging (ATRI) is a powerful approach for visualizing small molecules in live cells. We also developed a method, alkyne-tag Raman Screening (ATRaS), for identification of small molecule-binding site in protein. In this talk, I would like to introduce these methods and their application to chemical biology research.

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Keynote Speaker Dr. James (Jay) Bradner James (Jay) Bradner, M.D., joined Novartis on January 1, 2016 and became President of the Novartis Institutes for BioMedical Research (NIBR) on March 1, 2016. He is a member of the Executive Committee of Novartis.

Prior to joining Novartis, Dr. Bradner was on the faculty of Harvard Medical School in the Department of Medical Oncology at the Dana-Farber Cancer Institute in the United States from 2005 through 2015. Dr. Bradner is a co-founder of five biotechnology companies and has authored more than 250 scientific publications and 50 US patent applications.

President of the Novartis Institutes Dr. Bradner is a graduate of Harvard University and the University of Chicago Medical for BioMedical Research (NIBR) School in the US. He completed his residency in medicine at Brigham and Women’s Hospital and his fellowship in medical oncology and hematology at the Dana-Farber Cancer Institute. He has been honored with many awards and was elected into the American Society for Clinical Investigation in 2011 and the Alpha Omega Alpha Honor Medical Society in 2013. “Chemical Biology & Therapeutics” Disease biology research, on occasion, presents clarified opportunities for targeted therapeutic intervention. Regrettably, the discrete biomolecular target or target pathway is equally often just beyond the conceptual reach of traditional therapeutic modalities. The lowest hanging fruit (e.g. kinases, circulating proteins) is rapidly collected in a competitive race to potency, selectivity and index clinical proof-of-concept; then this research is systematically reconsidered by a commodity market of thinly differentiated fast-followers. Left behind are a growing number of highly compelling, albeit difficult, validated targets, that await a conceptual reconsideration and generational advance in the science of therapeutics. To organize around innovation in therapeutics science, we have created a new unit at the Novartis Institutes for BioMedical Research – Chemical Biology & Therapeutics. Our brand of chemical biology is unapologetically translational, seeing no barrier to atomically resolved mechanistic insights in the present study of human biology. This unit benefits from a legacy of contribution internally at NIBR and GNF in chemical genetics, allostery and modular therapeutic design, and the creativity of chemical biologists externally. In this seminar, I hope to share one thread of this investigation, namely the innovation of modular small-molecule therapeutics that engender non-natural protein-protein associations to short circuit disease biology in cancer and neuroscience, with overt implications more broadly in other disease areas. This talk will highlight progress in bifunctional protein degraders, molecular glues, covalent chemoproteomics and sequence-specific targeting of RNA by small molecules. Consideration of under-resourced opportunities as well as significant challenges will be defined, both in ligand discovery and pre-clinical therapeutic development. Finally, if time allows I will try to speak to how chemical biology may contribute to the innovation of SARS-CoV-2 therapeutics.

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Keynote Speaker Dr. Alanna Schepartz

Alanna Schepartz is the C.Z. and Irmgard Chu Distinguished Chair in the departments of Chemistry and Molecular and Cell Biology at the University of California, Berkeley. Her research group studies the chemistry and biology of complex cellular machines and exploits this knowledge to design or discover molecules–both small and large–with unique or useful properties. Dr. Schepartz obtained her undergraduate education in chemistry at the State University of New York, Albany. She earned a Ph.D. from Columbia University under the direction of Ronald Breslow, and spent two years as an NIH Postdoctoral Fellow at Caltech working with Peter Dervan. Professor Schepartz joined the faculty at Yale in 1988 and was named a Sterling Professor, Yale’s highest faculty honor, in 2017. In 2019 Professor Schepartz and her laboratory moved to the University of California, T.Z. and Irmgard Chu Berkeley. Her honors include a Packard Fellowship in Science and Engineering, an NSF Distinguished Chair in Chemistry, Presidential Young Investigator Award, the Eli Lilly Award in Biological Chemistry, an Professor of Molecular and Cell ACS Cope Scholar Award, the ACS Chemical Biology Prize, the Ralph F. Hirschmann Biology, University of California, Award in Peptide Chemistry, the Ronald Breslow Award for Achievement in Biomimetic Berkeley Chemistry, the Frank H. Westheimer Prize, and the Wheland Medal. She is a member of the American Academy of Arts and Sciences and the National Academy of Sciences.

“Novel molecules from a repurposed translation machine” Polymers of one form or another power all living organisms and many technologies that advance industry and medicine. But today, our ability to rationally design and evolve new polymers (including wholly non-natural proteins) is largely limited to the few natural backbones for which nature has provided a genetic code. Our group is part of a large, collaborative effort–an NSF Center for Chemical Innovation–to exploit the natural translation apparatus to generate new families of sequence-defined, chemical polymers that bear only a glancing resemblance to those encoded by nature. This lecture will describe recent progress in the application of chemical, synthetic, structural, and computational biology tools to support the biosynthesis of sequence-defined polymersin vivo and in vitro.

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Keynote Speaker Dr. Stuart Schreiber Stuart Schreiber is the Morris Loeb Professor of Chemistry and Chemical Biology at Harvard University, a co-Founder of the Broad Institute, and a member of the National Academy of Sciences, National Academy of Medicine and American Academy of Arts and Sciences.

His lab integrates chemical biology and human biology to advance the science of therapeutics. He is known for having developed systematic ways to explore biology, especially disease biology, using small molecules and for his role in the development of the field of chemical biology. Key advances include the finding Morris Loeb Professor of Chemistry and Chemical that small molecules can function as “molecular glues” that promote protein– Biology at Harvard University, a protein interactions, the discovery of mTOR and its role in nutrient-response co-Founder of the Broad Institute signaling, and the discovery of histone deacetylases and that chromatin marks regulate gene expression. His research has been acknowledged through awards including the Wolf Prize in Chemistry and the Arthur Cope Award. His approach to therapeutics discovery guided the development of many biotechnology companies that he founded including Vertex Pharmaceuticals and Ariad Pharmaceuticals.

“30 years of Molecular Glues: Controlling Cell Circuitry in Biology and Medicine” This coming year marks the 50th and 35th anniversaries of the reporting of the natural products and immunosuppressants cyclosporin A (CsA; sandimmune) and FK506 (tacrolimus), respectively, and the 30th anniversary of the revelation, published in Cell in 1991, that both compounds act in a way previously not seen – as “molecular glues” that induce protein–protein associations. On this occasion, and as the realization that additional transformative medicines also act as molecular glues continues to fuel the surge of interest in diverse chemical strategies for inducing functional protein–protein associations, I will explore the arc of this story and present new advances in the discovery of small-molecule binders and molecular glues.

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Keynote Speaker Dr. Herbert Waldmann Dr. Herbert Waldmann was born in Neuwied, Germany and studied chemistry at the University of Mainz where he received his PhD in organic chemistry in 1985 under the guidance of Horst Kunz. After a postdoctoral appointment with George Whitesides at Harvard University, he completed his habilitation at the University of Mainz in 1991. In 1999 he was appointed Director at the Max Planck Institute of Molecular Physiology Dortmund and Professor of Organic Chemistry at the University of Dortmund. His research interests lie in the syntheses of signal transduction modulators and the syntheses of natural product inspired compound libraries and their biological evaluation.

He has been the recipient of the Friedrich Weygand Award for the advancement of peptide chemistry, of the Carl Duisberg Award of the Gesellschaft Deutscher Chemiker, Director at the Max Planck the Otto-Bayer-Award, the Steinhofer Award of the Steinhofer Foundation, the Institute of Molecular Physiology Max Bergmann Medal, the GSK Award on Chemical Biology, the Hans-Herloff Dortmund and Professor of Inhoffen-Medal, the Emil-Fischer-Medal, he is a Member of “Deutsche Akademie der Organic Chemistry at the Naturforscher Leopoldina, Halle/Saale”, of the NRW Akademie der Wissenschaft und University of Dortmund. der Künste and since 2005 he is a Fellow of the Royal Society of Chemistry. In 2014 he received the Honorary Doctorate (Dr. h. c.) bestowed by Leiden University, NL.

“Pseudo Natural Products – Chemical Evolution of Natural Product Structure” Natural products have provided inspiration for chemical biology ring-distortion natural products BIOS

O HO 1 H R N 2 and medicinal chemistry research. However, their often complex N N N N R 1 R H H H N 4 N H R 3 structure, and, therefore, demanding synthesis as well as their H R N O MeO2C OH frequent unavailability, hamper their application. NP-derived compounds NP-inspired compounds N O H OH N O N H This raises the fundamental question whether the particular Ac OMe structural and biological properties of natural products can be H C5H11 O translated to structurally less demanding compounds, readily accessible pseudo-natural products O by chemical synthesis and yet still endowed with pronounced bioactivity. H N HN HN NH NH N H H The lecture will describe a logic for the simplification of natural N O O NH N NH product structure by means of “Biology Oriented Synthesis” (BIOS) O H and its evolution into the “Pseudo Natural Product” (PNP) concept. Unprecedented combinations of NP fragments Novel scaffolds Application of natural product inspired compound collections designed and synthesized following these principles in cell-based Concept: Nat. Chem. 2020, 12, 227; Nat. Chem. 2018, 10, 1103; Cell phenotypic assays and subsequent identification of the cellularChem. Biol. 2019, 24, 512; Angew Chem. Int. Ed. 2019, 58, 14715; target proteins demonstrate that the BIOS and PNPs may enable 2019, 58, 17016 innovation in both chemical biology and medicinal chemistry research.

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Session 1: In-Cell Chemistry “Expanding the activity-based Dr. Keriann Backus chemoproteomic toolbox”

Bioorthogonal chemistry is a mainstay of chemoproteomic sample preparation workflows. Alexander and Renee Kolin While numerous transformations are now available, Term Chair, Assistant Professor, chemoproteomic studies still rely overwhelmingly Biological Chemistry, Chemis- on copper(I)-catalyzed azide–alkyne cycloaddition try, & Biochemistry UCLA (CuAAC) or ‘click’ chemistry. In this seminar, I will discuss the use of Suzuki–Miyaura cross-coupling for gel-based activity-based protein profiling (ABPP) and Keriann Backus is an Assistant Professor of Biological mass-spectrometry-based chemoproteomic profiling. Chemistry and Chemistry and Biochemistry and Key findings highlighted will include the identification Alexander and Renee Kolin Term Chair at the of reaction conditions that proceed in complex cell University of California, Los Angeles. Her research lysates and a comparison of Suzuki–Miyaura cross- interests include the developing of new chemical coupling and CuAAC for chemoproteomics, including probes, chemoproteomic and proteogenomic methods for target deconvolution studies. Uniquely enabled by to study and rewire protein function in health and observed orthogonality of palladium-catalyzed cross- disease. coupling and CuAAC, I will also discuss applications Dr. Backus received a BS in Chemistry and BA of this chemistry to dual labeling experiments. in Latin American Studies in 2007 from Brown University. Her doctoral research was conducted in the laboratories of Benjamin Davis (Oxford) and Clifton Barry (NIH, NIAID) as a 2007 Rhodes Scholar and an NIH Oxford Cambridge Scholar. Her PhD work focused on the development of chemical probes to label and image Mycobacterium tuberculosis. In 2012, Backus completed her doctorate and began an NIH postdoctoral fellowship at The Scripps Research Institute in the laboratory of Benjamin Cravatt. Her postdoctoral research developed chemoproteomic methods for the proteome-wide identification of ligandable cysteine and lysine residues. At UCLA, Dr. Backus’s research has been recognized by numerous awards, including a Beckman Young Investigator Award, DARPA Young Faculty Award, and a V Scholar Research Award.

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Session 1: In-Cell Chemistry “A Small-Molecule Targeted RNA Dr. Gonçalo Bernardes Degradation Approach: Empowering RNA Methylation Analysis”

The fates of RNA species in a cell are controlled by Reader in Chemical Biology, ribonucleases, which degrade them by exploiting the Department of Chemistry, universal structural 2’-OH group. This phenomenon University of Cambridge, UK plays a key role in numerous transformative Instituto de Medicina technologies, e.g. RNA interference and CRISPR/ Molecular, Lisbon, Portugal Cas13-based RNA editing systems. These approaches, however, are genetic or oligomer-based so have inherent limitations. This lecture will cover our efforts After completing his D.Phil. in 2008 at the University towards the development of small molecules capable of Oxford, U.K., he undertook postdoctoral work at of degrading nucleic acids in a targeted manner. the Max-Planck Institute of Colloids and Interfaces, Germany, and the ETH Zürich, Switzerland, and worked as a Group Leader at Alfama Lda in Portugal. He started his independent research career in 2013 at the University of Cambridge as a Royal Society University Research Fellow. In 2018 he was appointed University Lecturer (Tenured) and recently has been promoted to Reader (Associate Professor). Gonçalo is the recipient of two European Research Council grants; a starting grant and a proof-of-concept grant, and was awarded the Harrison–Meldola Memorial Prize in 2016 and the MedChemComm Emerging Investigator Lectureship in 2018, both from the Royal Society of Chemistry. His research group interests focus on the use of chemistry principles to tackle challenging biological problems for understanding and fight cancer.

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Session: In-Cell Chemistry Chemistry Emerging Investigator (2017), Dream Dr. Justin Chalker Chemistry Award Finalist (1 of 5 globally, 2017), the Organic and Biomolecular Chemistry New Talent Award (2018), Eureka Prize Finalist for Outstanding Early Career Research (1 of 3 in Australia, 2018), the SA Science Excellence Awards STEM Educator of the Associate Professor and Research Leader Institute Year (2018), and the AMP Tomorrow Maker fellowship for Nanoscale Science and (2018). Technology Flinders University Adelaide, Australia “The chemical biology of cysteine oxidation”

Justin M. Chalker earned a B.S. in Chemistry and a B.A. in the History and Philosophy of Science at The University of Pittsburgh in 2006. At Pittsburgh, under the direction of Theodore Cohen, he contributed to the total synthesis of the marine natural products (-)-erythrodiene and (-)-kainic acid. Supported by a Rhodes Scholarship and a National Science Foundation Cysteine sulfenic acid is thought to be a biomarker for Graduate Research Fellowship, Justin then completed oxidative stress and associated diseases, but we have an his D.Phil. at the University of Oxford under the incomplete understanding of which proteins contain supervision of Benjamin Davis where he developed this group and what this means for cellular function several tools for the site-selective modification of and physiology.1 One challenge in mapping cysteine proteins, many of which are now commercialised. sulfenic acid is the paucity of probes that react both In 2012, Justin started his independent career as an rapidly and selectively with this functional group assistant professor at The University of Tulsa where inside the cell.1,2 Our research team has recently used he established a diverse research program in organic norbornene derivatives to trap cysteine sulfenic acid chemistry, biochemistry and material science. In on small molecules, purified proteins, and proteins 2015, Justin moved to Flinders University as a in living cells.1-5 Enrichment of these proteins and Lecturer in Synthetic Chemistry and recipient of an subsequent proteomics analysis has revealed 148 ARC Discovery Early Career Researcher Award. In proteins previously unknown to form cysteine sulfenic 2017, Justin was promoted to Senior Lecturer and acid during oxidative stress.5 I will discuss potential Research Leader in the Institute for Nanoscale Science implications of these discoveries with respect to and Technology at Flinders University and then to fundamental biochemistry, new diagnostic tools, and Associate Professor in 2019. Justin has earned >$3M leads for medicinal chemistry. AUD in competitive funding for his scholarly activities 1. Chem. Soc. Rev. 2018, 47, 231-268 2. Curr. Opin. Chem. Biol. 2021, 60, 55-65 and he has been recognised with several awards for 3. Tetrahedron 2018, 74, 1220-1228 his efforts in teaching and research. These include the 4. ACS Chem. Biol. 2019, 14, 594-598 South Australian Tall Poppy of the Year (2016), Green 5. ChemBioChem 2020, 21, 1329-1334

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Session 2: COVID-19, Disease Modeling, and Drug Discovery “Repurposing FDA-Approved Drugs Dr. Shuibing Chen for COVID-19” There is an urgent need to create novel models using human disease-relevant cells to study SARS-CoV-2 biology and to facilitate drug screening. As SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid Kilt Family Associate Professor, model using human pluripotent stem cells (hPSC-LOs). Weill Cornell Medicine The hPSC-LOs, particularly alveolar type II-like cells, are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. Nearly 25% of these patients also have gastrointestinal manifestations, Dr. Shuibing Chen is the Kilts Family Associate Professor which are associated with worse COVID-19 outcomes1. (tenured) and the Director of Diabetes Program in the We therefore also generated complementary hPSC-derived Department of Surgery at Weill Cornell Medicine, New colonic organoids (hPSC-COs) to explore the response York. She received my B.S. and M.S. in Chemistry from of colonic cells to SARS-CoV-2 infection. We found that Tsinghua University in China. Then, she pursued my PhD multiple colonic cell types, especially enterocytes, express under the advisement of Dr. Peter G. Schultz at the Scripps ACE2 and are permissive to SARS-CoV-2 infection. Using Research Institute. After graduation, she joined Dr. Doug hPSC-LOs, we performed a high throughput screen of FDA- Melton’s laboratory at Harvard University to study the approved drugs and identified entry inhibitors of SARS- directed differentiation of human embryonic stem cells CoV-2, including imatinib, mycophenolic acid (MPA), toward pancreatic lineage. and quinacrine dihydrochloride (QNHC). Treatment at The major research interest in the Chen Laboratory at Weill physiologically relevant levels of these drugs significantly Cornell Medicine focuses on studying the role of genetic inhibited SARS-CoV-2 infection of both hPSC-LOs and factors and environmental factors on pancreatic beta cell in hPSC-COs. Together, these data demonstrate that hPSC- type 1 and 2 diabetes. Dr, Chen has published more than LOs and hPSC-COs infected by SARS-CoV-2 can serve as 40 papers on peer-reviewed high impact journals, such as disease models to study SARS-CoV-2 infection and provide Nature Medicine, Cell Stem Cell, Nature Chemical Biology, a valuable resource for drug screening to identify candidate etc. She has received many awards including New York Stem COVID-19 therapeutics. Cell Foundation Robertson Investigator, American Diabetes Association (ADA) Junior Faculty Award, ADA Innovative “What you will learn” bullet points Award, NIH Director’s New Innovator Award, American • Human pluripotent stem cell-derived colon and lung organoids provide useful models to study SARS-CoV-2 infection. Association for Cancer Research Career Development • 10X scRNA-seq is a powerful tool to study colon and lung Award, and ISSCR Dr. Susan Lim Award for Outstanding organoids. Young Investigator, etc. • hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and for drug screening.

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Session 2: COVID-19, Disease Modeling, and Drug Discovery “Developing Agents to Mitigate the Systemic Dr. Nigel H. Greig and Neurological Inflammatory Component of COVID-19” The innate immune response is one of our primary defenses against pathogens, misfolded proteins and a wide variety of Chief, Drug Design & pathological insults that induce cellular dysfunction and Development Section, demise. Its time-dependent regulation involves an initial Intramural Research Program, proinflammatory phase aimed to neutralize the danger, National Institute on Aging, followed immediately by an anti-inflammatory phase National Institutes of Health to restore tissue homeostasis by activating regenerative processes. This dualism occurs systemically as well as within the central nervous system to support rapid and Nigel Greig was trained as a pharmacologist with a efficient tissue repair. However, an unregulated, persistent background in medicinal chemistry and physiology, and and chronic proinflammatory response can induce cellular gained his Ph.D. from the Royal College of Surgeons, dysfunction and death. Indeed, neuroinflammation University of London, England. The research portion of his instigated by microglial cell activation is associated with both Ph.D. was completed under the mentorship of Prof. Kurt chronic and acute neurodegenerative disorders, epitomized Hellmann. by Alzheimer’s disease (AD) and traumatic brain injury In 1982, Nigel joined the Laboratory of Neuroscience within (TBI), and drives disease progression. In the development the Intramural Research Program (IRP), National Institute of new agents to mitigate systemic and neuroinflammation on Aging (NIA), NIH, as a Post-doc in the US. In 1989, as a treatment strategy for AD and TBI, potent cytokine- Nigel was one of the initial scientists to join the California suppressing agents were generated on the backbone of the biotechnology company, Athena Neurosciences, which is immunomodulatory imide drugs (IMiDs) thalidomide now part of Perrigo. (Thal) and pomalidomide (Pom). Key features in these novel Returning to NIA as a tenured scientist in 1992, Nigel’s analogs involved selective thionation of carbonyl groups research has evolved into his present interest, the design to augment cytokine lowering action, focused on TNF-α and development of drugs for the treatment of degenerative and the replacement of the glutarimide ring common disorders prevalent in aging. He heads the Drug Design & to Thal and Pom, with a larger cage-like adamantyl ring Development Section within the Translational Gerontology structure to potentially reduce cereblon binding and the Branch, IRP, NIA, NIH, located in Baltimore, MD, USA. teratogenicity associated with Thal and Pom. In response In extensive studies with a small core of long-time, close to the COVID-19 crisis, and as a means to potentially collaborators, they have successfully moved multiple mitigate the ‘cytokine storm’ in the lung associated with the experimental drugs from concept through preclinical poor clinical outcome of those challenged with severe acute studies and into human clinical trials (Phenserine, Posiphen, respiratory syndrome coronavirus 2 (SARS-CoV-2), Thal, Bisnorcymserine, Exendin-4). Pom and novel analogs are being evaluated in cellular and animal models of viral challenge, particularly as adamantyl- containing drugs (adamantane, amantadine, rimantadine) are known to possess antiviral actions.

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Session 2: COVID-19, Disease Modeling, and Drug Discovery “Optogenetic alpha-synuclein aggregation Dr. Gabsang Lee system-based compound screening platform in PD hiPSC-derived mDA neurons”

Parkinson’s disease (PD) is characterized by pathogenic Associate Professor, Johns alpha-synuclein (α-syn) protein aggregates in and Hopkins University, School progressive loss of midbrain dopaminergic (mDA) of Medicine, Institute for Cell neurons. While human induced pluripotent stem cells Engineering, Departments of (hiPSCs) provide strategic advantages to study PD, key Neurology and Neuroscience pathogenic α-syn characters are not observed in PD hiPSC-derived neurons. In this study, we developed Dr. Gabsang Lee is an Associate Professor in the an optogenetics-assisted method of alpha-synuclein Department of Neurology/Neuroscience and Institute aggregation induction system (OASIS) that can for Cell Engineering (ICE) at the Johns Hopkins optically aggregate α-syn in a light dose-dependent University School of Medicine. He obtained his B.S., manner and an exceptionally short temporal window. D.V.M., Ph.D. degrees in Veterinary Medicine at the OASIS leads to phosphorylation of α-syn aggregates, Seoul National University, South Korea. After his makes them insoluble, and induces cellular toxicity in post-doctoral training at Sloan Kettering Institute PD hiPSC-derived mDA neurons. As a proof of concept, (New York,) he joined the faculty of Johns Hopkins as we conducted OASIS-based compound screening in Assistant Professor (2011). Dr. Lee is one of the first human neuronal cells and identified two candidate researchers who utilized induced pluripotent stem small molecules that considerably delay/decrease the cells (iPSCs) for disease modelling and drug discovery/ pathogenic α-syn characters and significantly rescue validation. The international scientific community the neurotoxicity in PD hiPSC-derived mDA neurons. recognizes and values Dr. Lee’s knowledge, and this Our OASIS system provides new research and drug is exemplified by many awards he received including screening platform for PD as well as many diseases the Druckenmiller Postdoctoral Fellowship and the with aberrant protein aggregations. Robertson Investigator Award from the New York Stem Cell Foundation, and his active participation in journal peer review activities and domestic/ international research grant programs in the area of stem cell research, neurodegenerative diseases, and high throughput screening. He has been invited as a speaker >100 conferences in US and international locations.

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Session 2: COVID-19, Disease Modeling, and Drug Discovery “Modeling viral infection and screening Dr. Zhexing Wen therapeutic compounds with human iPSC- derived neural cells and brain organoids”

Human induced pluripotent stem cells (iPSCs), Assistant Professor, reprogrammed from somatic cells of healthy subjects Department of Psychiatry and or patients, have the capacity to differentiate into Behavioral Sciences, Emory virtually any cell type in the human body. Since University human iPSCs provide a renewable source of previously inaccessible, disease-relevant human cell types, iPSC technology has offered an unprecedented opportunity Dr. Zhexing Wen, received his PhD training at the to model human development and diseases, screen Rutgers University in 2008 and his postdoctoral for therapeutic drugs, and develop cell replacement training at Johns Hopkins University 2009-2015. In therapies. Here we use human iPSC-derived neural 2016, Dr. Wen joined the Department of Psychiatry cells and 3-D brain organoids to study the impact of and Behavioral Sciences at Emory University as viral infection on the nervous system, including Zika an Assistant Professor, focusing on using human virus (ZIKV) and SARS-CoV-2. We found that ZIKV induced pluripotent stem cells (iPSCs) to elucidate can efficiently target human neural progenitor cells the biological functions of genetic and environmental (NPCs) and attenuate their growth. ZIKV infection risk factors in neurological and psychiatric disorders, of brain organoids leads to reduced NPC layer and identify pathological developmental processes that neuronal layer thickness, and an overall reduction in may contribute to the etiology of these complex organoid size, consistent with features of microcephaly. diseases, and translate such knowledge into In addition, astrocytes can be productively infected by therapeutic targets for developing novel treatments. ZIKV, which triggers antiviral response and cytokine production. We further performed a drug repurposing screen of ~6,000 compounds and identified leading compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in human iPSC-derived neural cells. Moreover, we are using human iPSC-derived neural cells and brain organoids to study the neurotropism of SARS-CoV-2. Our study also provides a tractable experimental model system for investigating the impact and mechanism of viral infection on human brain development and function, as well as a platform for therapeutic development.

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Session 3: Academic-Industry Partnerships case studies “NanoBRET Target Engagement to Dr. Tim Willson Illuminate the Dark Kinome” Kinases are highly successful drug targets, despite the challenge of achieving selectivity with small molecule inhibitors. Kinase target engagement and selectivity Research Professor, UNC is usually optimized using purified kinase domains in Eshelman School of Pharmacy, cell-free assay formats that routinely fail to correlate University of North Carolina with the potency of inhibition in live cells. To address at Chapel Hill CSO, Structural this gap, we developed a panel of fluorescent small Genomics Consortium at UNC molecule probes to enable NanoBRET assays that measure live cell target occupancy for the majority Dr. Willson is a Research Professor at the Eshelman of the human kinome (including hundreds of poorly School of Pharmacy, University of North Carolina at studied ‘dark’ kinases). Using these NanoBRET Chapel Hill and Chief Scientist of the SGC-UNC site. assays, we determined that kinase target engagement He has over 25 years of experience in pharmaceutical potencies of known drugs correlated with biomarkers research with a track record in discovery of first in of clinical activity, supporting the predictive potential class clinical candidates. He led the Glaxo program of the NanoBRET method for lead optimization. on orphan nuclear receptors that used chemical The cyclin-dependent kinase (CDK) family comprises biology to uncover their role in regulation of human 21 phosphotransfer enzymes with diverse cellular metabolism. He was codiscoverer of the FXR agonist functions, including regulation of the eukaryotic cell obeticholic acid, an FDA-approved breakthrough cycle, key aspects of gene transcription. FDA-approval drug for liver diseases. He is widely recognized of dual CDK4/6 inhibitors for treatment of HER2 for scientific leadership in chemical biology and negative breast cancer has amplified broader interest was named one of the world’s 400 most influential in exploring the therapeutic potential of the CDK biomedical researchers. Dr. Willson has been a long- family with small molecule inhibitors. The CDKs often time supporter of precompetitive chemistry in early require heterodimerization with a cyclin protein to drug discovery and was an early advocate of the SGC form an active enzyme. This regulation is dynamic, Chemical Probes project. His current laboratory at as CDK/cyclin interactions oscillate depending on UNC works closely with pharma companies and the cell cycle, providing a unique layer of complexity academic investigators to develop small molecule to intracellular signaling mediated by this kinase chemical probes for dark kinases that are openly shared subfamily. We developed NanoBRET assays for all 21 with the scientific community. Current research has CDK family members and defined the landscape of led to the development of the Kinase Chemogenomic inhibition across a collection of clinically-advanced Set (KCGS) that contains selective inhibitors of more inhibitors and chemical tools. These NanoBRET assays than 200 kinases. will aid the development of new chemical tools for the dark CDKs.

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Session 3: Academic-Industry Partnerships case studies “NanoBRET Target Engagement to Dr. Matthew Robers Illuminate the Dark Kinome” Kinases are highly successful drug targets, despite the challenge of achieving selectivity with small molecule inhibitors. Kinase target engagement and selectivity Senior Research Scientist and is usually optimized using purified kinase domains in Group Leader at Promega cell-free assay formats that routinely fail to correlate Corporation with the potency of inhibition in live cells. To address this gap, we developed a panel of fluorescent small molecule probes to enable NanoBRET assays that measure live cell target occupancy for the majority Matthew Robers is a Senior Research Scientist and of the human kinome (including hundreds of poorly Group Leader at Promega Corporation. Matthew studied ‘dark’ kinases). Using these NanoBRET received post-graduate training at University of assays, we determined that kinase target engagement Wisconsin-Madison, studying iron-sulfur cluster potencies of known drugs correlated with biomarkers enzymes in bacteria. Following graduate school, of clinical activity, supporting the predictive potential Matthew emphasized technology development of the NanoBRET method for lead optimization. for cellular pathway analysis at Life Technologies The cyclin-dependent kinase (CDK) family comprises (Invitrogen), where he led a platform to quantify post- 21 phosphotransfer enzymes with diverse cellular translational modifications in live cells. Since joining functions, including regulation of the eukaryotic cell Promega, Matthew has built a team focused on the cycle, key aspects of gene transcription. FDA-approval development of new technologies to assess intracellular of dual CDK4/6 inhibitors for treatment of HER2 target occupancy, and has developed biophysical negative breast cancer has amplified broader interest techniques for quantifying compound affinity and in exploring the therapeutic potential of the CDK engagement kinetics within intact cells. Matthew’s family with small molecule inhibitors. The CDKs often target engagement team is aggressively expanding the require heterodimerization with a cyclin protein to NanoBRET platform for complex intracellular targets form an active enzyme. This regulation is dynamic, in oncology, inflammation, and CNS disease. This as CDK/cyclin interactions oscillate depending on effort includes authoring peer reviewed publications the cell cycle, providing a unique layer of complexity and leading technology patents leveraging novel to intracellular signaling mediated by this kinase applications of luminescent detection chemistries. subfamily. We developed NanoBRET assays for all 21 CDK family members and defined the landscape of inhibition across a collection of clinically-advanced inhibitors and chemical tools. These NanoBRET assays will aid the development of new chemical tools for the dark CDKs.

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Session 3: Academic-Industry Partnerships case studies “Targeting Essential Plasmepsin Proteases Dr. Manuel de Lera Ruiz – An Efficient Academic/Industrial Collaboration toward the Next Generation of Antimalarial Agents”

Associate Principal Scientist, In this presentation will be described a successful Discovery Chemistry, West academia/industrial collaboration between The Walter Point, PA, Merck and Eliza Hall Institute (Australia) and Merck & Co, USA funded by the Wellcome Trust (UK). This work involves the discovery of novel aspartic protease inhibitors toward the treatment of malaria. Artemisin Manuel de Lera Ruiz received his B.Sc. in chemistry combination therapy (ACT) is the current main from the Universidad Autónoma of Madrid in 1997. treatment option for malaria, which is caused by the After completion of his Ph.D. in 2001 from the intracellular parasite Plasmodium. However, increased University of Nottingham, he joined Professor Leo resistance to ACT highlights the importance of finding A. Paquette research labs as a postdoctoral fellow. In new drugs with novel mechanisms of action. Herein will 2003, he started a career in Medicinal Chemistry at be described the discovery of drug-like dual inhibitors Schering-Plough Research Institute and currently, of PMIX and PMX, including WM382, a compound he is an Associate Principal Scientist in Discovery that blocks multiple stages of the Plasmodium life cycle Chemistry at Merck Research Laboratories in West that is efficacious in in vivo malaria mouse models Point, Pennsylvania. after oral administration.

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Session 3: Academic-Industry Partnerships case studies helped to build this company to > 150 scientists. In Dr. Douglas S. Auld 2004, he was hired by Francis Collins (Director of the U.S. National Institute of Health) to start the NIH Chemical Genomics Center (NCGC). At the NCGC, he worked to establish a center of scientific excellence, which has now become part of the National Center for Senior Principle Scientist, Novartis Institutes for Advancing Translational Sciences (1 of 27 Institutes Biomedical Research, and Centers at the NIH) with wide-reaching effects Cambridge, Massachusetts benefiting the improvement of human health as well as providing training to young scientists interested in biomedical research. You can also view his interview in Assays and Drug Development Technologies at: https:// Doug Auld joined NIBR in 2010. At NIBR, his lab www.ncbi.nlm.nih.gov/pmc/articles/PMC5116652/. provides assay development expertise and resources to support early stage drug development efforts. He also manages a lab at NIBR that provides resources and expertise in high-throughput biology to support external collaborations and have worked with multiple “Novartis FAST Lab: academic institutes in this effort. He has expertise Fostering Innovation in chemical biology in assay development, biochemistry, enzymology, through academic collaborations” cell-based assay designs, and high content imaging. He is a founding editor and contributor to the Assay This talk will describe the Novartis Facilitated Guidance Manual (AGM), an eBook available for Access to Screening Technology (FAST) lab that free on the NCBI web site which aims to capture the provides resources and expertise in early phase tribal knowledge of the pharmaceutical industry so drug discovery and technology development efforts. that others can learn from both successes and failures. The collaboration model will be shown which is a (https://www.ncbi.nlm.nih.gov/books/NBK53196/). truly “no-strings” attached mechanism to accelerate scientific collaborations with academic labs and will Dr. Auld completed his Ph.D. at UNC with Prof. illustrate how the model works with a few example Gary J. Pielak in the Dept. of Chemistry in 1993 and collaborations. did his post-doctoral training at MIT with Prof. Paul Schimmel studying tRNA synthetases (1994-1996). Following post-doctoral training, he decided to go to a fledging biotechnology company aimed at applying combinatorial chemistry to drug discovery and joined Pharmacopeia at an early stage (<20 scientists) and

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Session 3: Academic-Industry Partnerships case studies “Reimagining Druggability using Dr. Daniel K. Nomura Chemoproteomic Platforms”

The Nomura Research Group is focused on reimagining druggability using chemoproteomic Professor of Chemical Biology, platforms to develop transformative medicines. One of University of California, the greatest challenges that we face in discovering new Berkeley disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “ligandable hotspots” that small-molecules can bind to modulate protein Dan Nomura is a Professor of Chemical Biology in function. Our research group addresses this challenge the Departments of Chemistry, Molecular and Cell by advancing and applying chemoproteomic platforms Biology, and Nutritional Sciences and Toxicology at to discover and pharmacologically target unique the University of California, Berkeley and an Adjunct and novel ligandable hotspots for disease therapy. Professor in the Department of Pharmaceutical We currently have three major research directions. Chemistry at UCSF. Since 2017, he has also been Our first major focus is on developing and applying the Director of the Novartis-Berkeley Center for chemoproteomics-enabled covalent ligand discovery Proteomics and Chemistry Technologies focused approaches to rapidly discover small-molecule on using chemoproteomic platforms to tackle the therapeutic leads that target unique and novel undruggable proteome. He is also Co-Founder and ligandable hotspots for undruggable protein targets Head of the Scientific Advisory Board of Frontier and pathways. Our second research area focuses Medicines. Since 2018, he has also been an Associate on discovering and exploiting unique therapeutic Editor for Cell Chemical Biology. He earned his B.A. modalities accessed by natural products. Our third in Molecular and Cell Biology and Ph.D. in Molecular research area focuses on using chemoproteomics- Toxicology at UC Berkeley with Professor John Casida enabled covalent ligand discovery platforms to expand and was a postdoctoral fellow at Scripps Research with the scope of targeted protein degradation and to Professor Ben Cravatt before returning to Berkeley discover new induced proximity-based therapeutic as a faculty member in 2011. Among his honors modalities. Collectively, our lab is focused on are selection as a Searle Scholar, American Cancer developing next-generation transformative medicines Society Research Scholar Award, the Department of through pioneering innovative chemical technologies Defense Breakthroughs Award, Eicosanoid Research to overcome challenges in drug discovery. Foundation Young Investigator Award, and the Mark Foundation for Cancer Research ASPIRE award.

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Session 4: Chemical Biology of Small Molecule Protein Degraders “Introduction: Targeted Protein Dr. Andrew Zhang Degradation at AstraZeneca”

Targeted protein degradation has advanced rapidly in the last few years and has emerged as a therapeutic Team Leader in the Chemical modality, particularly for difficult to drug targets. In Biology Department at the process, Chemical biology has made a profound AstraZeneca impact in the development of small molecule protein degraders, in particular providing the tools for comprehensive mechanistic studies around cellular protein degradation and dynamics, as well as ternary Andrew Zhang is a Team Leader in the Chemical complex formation. This presentation introduces the Biology Department at AstraZeneca. He joined session by discussing the assays involved in developing AstraZeneca in 2013 with research interests in target a protein degradation cascade as part of AstraZeneca’s deconvolution, particularly using chemical proteomics protein degradation strategy. and orthogonal methods for identifying target engagement events and profiling selectivity. He is now leading the proteomics efforts around profiling the selectivity and mechanism of small molecule protein degraders. Andrew trained at the interface of chemistry and molecular and cell biology, obtaining a B.S. in Chemistry and a B.A. in Molecular and Cell Biology from the University of California, Berkeley, followed by Ph.D. studies with Professor David Spiegel at Yale University around small molecule immunomodulators. Prior to joining AstraZeneca, Andrew carried out postdoctoral trainings with the Drug Discovery Group at the Ontario Institute for Cancer Research (Toronto, Canada) with Dr. Rima Al-awar.

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Session 4: Chemical Biology of Small Molecule Protein Degraders PF-06651600 (ritlecitinib), a covalent JAK3/Tec inhibitor Dr. Adam Gilbert currently in Phase 2b/3 trials for Alopecia Areata. Adam is currently a Senior Director in in charge of Pfizer’s Design and Synthesis Sciences (DSS) Group. DSS is platform medchem group located in Pfizer’s Discovery Sciences Department in Senior Director in charge of Groton, CT which helps drive key Pfizer initiatives such as Pfizer’s Design and Synthesis protein degradation, DNA-encoded library chemistry and Sciences (DSS) Group, selection analysis, phenotypic screening, vaccine protein Medicine Design, Pfizer, design, small molecule purification and small molecule Eastern Point Road, Groton, NMR. CT 06340

Adam Gilbert was born in New York City and raised in “BTK Protein Degradation: Delineating the Chappaqua, NY in Westchester County. He graduated cum laude/with honors with a B.A. in chemistry from Role of Cooperativity in the Design of Potent Haverford College. He received his Ph.D. with Professor PROTACs” Thomas Katz at Columbia University in 1992 where he worked on preparing novel helical metallocene conductors Proteolysis targeting chimeras (PROTACs) are and catalysts. After a postdoc with Professor William Wulff heterobifunctional molecules that simultaneously bind at the University of Chicago, he joined Medical Research to a target protein and an E3 ligase, thereby leading to Division of American Cyanamid in Pearl River, NY which ubiquitination and subsequent degradation of the target. became Wyeth Research. PROTACs not only eliminate the catalytic function of the At Wyeth, Adam worked in several therapeutic areas: targeted protein but also the protein scaffolding function metabolic diseases, antibacterials, neuroscience, oncology thereby allowing enabling biological effects previously and inflammation. His main contribution was managing thought to be undruggable. As a relatively new drug the Exploratory Chemistry Neuroscience portfolio where modality, fundamental questions remain regarding the he was directly responsible for developing lead matter from most important factors for achieving potent degradation HTS to Lead Optimization for the following programs and selectivity over related targets. Here we employ a which produced candidate molecules: PARP1 inhibitors, series of biochemical and cellular techniques to investigate mGluR5 negative allosteric modulators, and α7 agonists requirements for efficient knockdown of Bruton’s tyrosine and PAMs. kinase (BTK), a nonreceptor tyrosine kinase essential for B Adam joined the Pfizer in February 2010 as an Associate cell maturation. A library of BTK PROTACs were prepared Research Fellow and a labhead in charge of the Experimental and investigated for their ability to form binary and ternary Design Chemistry (EDC) – a group that focused on key complexes with BTK and cereblon (CRBN). Results were portfolio projects with challenging medicinal chemistry extended to measure effects on BTK–CRBN cooperative design issues including covalent inhibitors, allosteric interactions as well as in vitro and in vivo BTK degradation. GPCR modulators and chemoproteomics. EDC helped Our data show that cooperative ternary complex binding drive candidate molecule discovery for programs in Rare between BTK, PROTACs and CRBN is not necessary to Diseases, Neuroscience and Immunology highlighted by achieve potent BTK degradation.

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Session 4: Chemical Biology of Small Molecule Protein Degraders “Cellular Mechanistic Profiling of Dr. Danette Daniels Degradation Compounds”

• Monitoring of live cell kinetic protein degradation • Correlation of degradation profiles to ternary R&D Group Leader of complex formation and ubiquitination Functional Proteomics at • Cell-based assay strategies for rank ordering Promega Corporation compound potency and efficacy

Danette received her B.A. from Columbia University, Ph.D. in Biophysics from Yale University, and completed a postdoctoral fellowship at Stanford University School of Medicine studying the biophysical and biochemical mechanisms of the Wnt signaling pathway. She has been at Promega Corporation for 15 years and is currently an R&D Group Leader of Functional Proteomics. She leads a team developing technologies and performing research to understand dynamic intracellular interactions within the focus areas of epigenetics, targeted protein degradation, and drug discovery.

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Session 4: Chemical Biology of Small Molecule Protein Degraders organic chemistry and computational biology, and is Dr. Georg Winter supported by several national and international grants and fellowships including an ERC Starting Grant. Dr. Winter’s contribution to the field of targeted protein degradation was acknowledged via multiple prices and awards, including the prestigious Eppendorf Award Principal Investigator, CeMM- Center for Molecular Medicine 2019 and the Elisabeth Lutz Award of the Austrian of the Austrian Academy of Academy of Sciences. Science “Discovery and Characterization of Novel Molecular Glue Degraders” Georg Winter, PhD, obtained his degree from the Targeted protein degradation (TPD) is a new Medical University of Vienna, working on elucidating therapeutic modality based on drugs that destabilize the mechanism of action of anti-neoplastic drugs proteins by inducing their proximity to E3 ubiquitin under the supervision of Prof. Giulio Superti-Furga. He ligases. I will first discuss how we leverage TPD to specialized on proteomics- as well as chemical genetics understand transcriptional processes at a high kinetic approaches to identify drug resistance mechanisms resolution. Moreover, I will discuss how we develop and synergistic drug combinations. He continued his phenotypic drug screens to find novel small molecule training in chemical biology, working as a postdoctoral degraders that function as “molecular glues”. Molecular fellow with Dr. James Bradner the Dana Farber Cancer glues are of particular interest as they can degrade Institute/Harvard Medical School. Supported by an otherwise unligandable proteins by orchestrating direct EMBO fellowship, he innovated the first generalizable interactions between target and ligase. I will describe a pharmacologic solution to in vivo target protein scalable strategy toward glue degrader discovery that degradation (Winter et al., Science 2015). He was is based on chemical screening in hyponeddylated recruited as a CeMM Principal Investigator in June cells coupled to a multi-omics target deconvolution 2016 where his research is now focused on using the campaign. This approach led us to identify compounds unique molecular pharmacology of targeted protein that induce ubiquitination and degradation of cyclin degradation to understand and disrupt fundamental K by prompting an interaction of CDK12–cyclin K principles of transcription and gene control aberrantly with a CRL4B ligase complex. Notably, this interaction regulated in human cancers. Georg Winter (co-) is independent of a dedicated substrate receptor, thus authored 35 manuscripts including publications in functionally segregating this mechanism from all Science, Nature, Nature Chemical Biology, Nature described degraders. Collectively, our data outline a Genetics, Elife and Molecular Cell. His interdisciplinary versatile and broadly applicable strategy to identify research lab consists of 6 Postdocs, 4 graduate students degraders with nonobvious mechanisms and thus and 3 technical assistants trained in molecular biology, empower future drug discovery efforts.

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EFMC Speaker “From covalent inhibitors to Dr. Nir London covalent PROTACs”

Covalent inhibitors can display unmatched potency, Senior Scientist (Asst. prof.) selectivity and duration of action; however, their Dept. of Organic Chemistry discovery is challenging. Our lab develops technologies Weizmann Institute of Science for covalent ligand discovery including covalent virtual Rehovot, Israel. screening, automatic derivatization of covalent analogs starting from reversible ligands and empirical covalent fragment screening. Using covalent inhibitors one can theoretically target proteins traditionally considered Dr. Nir London received his PhD from the Hebrew ‘undruggable’. We have recently explored the University in 2011. He joined the Department of opportunity to marry Proteolysis Targeting Chimeras Pharmaceutical Chemistry at the University of (PROTACs) with covalent binding. While irreversible California, San Francisco, as an EMBO post-doc fellow binding should negate the sub-stoichometric starting in 2012, and joined the Weizmann Institute as efficiency offered by PROTACs, reversible covalent a senior scientist in 2015. Dr. London’s lab is focused PROTACs can potentially benefit the best of both on covalent chemical biology and drug discovery and worlds. We designed and tested a series of reversible has developed several technologies for the design of and irreversible BTK PROTACs, the best of which covalent inhibitors. His honors include the Chorev were amongst the most potent demonstrated to date, Award by the Israeli Chemical Society, the Dimitris with efficacy in patient samples. To facilitate design N. Chorafas Foundation Award, a postdoctoral award of optimal PROTAC linkers we have also developed from the Program for Breakthrough Biomedical PRosettaC -a holistic computational pipeline for Research. Most recently he also received the Alon modelling of putative PROTAC mediated quaternary fellowship, an award of excellence from the Israel complexes and PROTAC-DB a database of close to Cancer Association and the Breast Cancer Research 1,000 published PROTACs. Together we hope these Foundation – AACR Career Development Award for will facilitate the next generation of reversible covalent Translational Breast Cancer Research and selected for PROTACs. the IUPAC periodic table of young chemists.

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Session 5: Chemical Technologies to Promote Drug Discovery “A Chemoenzymatic Platform for the Dr. Hans Renata Production of Covalent Inhibitor Natural Products and Analogs Thereof”

By virtue of their unrivaled selectivity profiles, enzymes Assistant Professor, possess remarkable potential to address unsolved The Scripps Research Institute challenges in chemical synthesis. The realization of this potential, however, has only recently gained traction. Recent advances in enzyme engineering and genome mining have provided a powerful platform for identifying and optimizing enzymatic Hans Renata received his B.A. degree from Columbia transformations for synthetic applications and allowed University in 2008 and earned his Ph.D. from The us to begin formulating novel synthetic strategies Scripps Research Institute in 2013 under the guidance and disconnections. This talk will describe our recent of Prof. Phil S. Baran. After postdoctoral studies efforts in developing a new design language in chemical with Prof. Frances H. Arnold at Caltech, he began synthesis that centers on the application of biocatalytic his independent career at The Scripps Research retrosynthetic logic. Case studies will focus on the Institute in 2016. His research focuses on synthetic use of this platform in the chemoenzymatic syntheses and biosynthetic studies of natural products and of bioactive natural products that act as covalent biocatalytic reaction developments. inhibitors of their targets, as well as interrogation into their cellular targets through probe development and medicinal chemistry.

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Session 5: Chemical Technologies to Promote Drug Discovery Society (APS), Australian Peptide Society, Japanese Dr. Monika Raj Peptide Society, and the German Science Foundation.

“Chemical Tools for Selective Detection of Monomethyl Lysine PTMs” Associate Professor, Selective modification of biomolecules provides Department of Chemistry, scientists with an effective tool for a multitude Emory University of bioanalytical, therapeutic, biological and bioengineering applications. However, chemical strategies that can target a particular functional group at a single site in the presence of reactive amino Monika Raj completed her Ph.D. in Organic Chemistry acid side chains on protein surfaces are limited. We at the Indian Institute of Technology, Kanpur. Following have developed a multicomponent bioconjugation postdoctoral work at the University of Pennsylvania approach for selective labeling of proteins containing and New York University. Raj joined the faculty at secondary amines. This method does not require Seton Hall University, NJ, in 2014 and then moved to any genetic engineering of the protein target and Auburn University in 2017 before moving to Emory protection of the side chains of other amino acids. University as an Associate Professor in 2020. The resulting bioconjugation reaction leads to the Much of Monika Raj’s research focuses on understanding formation of a highly stable C-C bond at the site of the the roles proteins play in various physiological and conjugation. The broad utility of the bioconjugation pathological processes and utilizes this knowledge to reaction is demonstrated by conjugation of various identify novel therapeutic targets and drugs to treat probes such as dye, peptides, and PEG on different diseases. To achieve these goals, Raj focuses on the proteins containing a proline at the N-terminus development of novel chemical probes, cyclic peptides, such as creatine kinase and aldolase. This method is synthetic strategies, and imaging tools that draw from employed for labeling monomethyl lysine containing core disciplines of organic and biological chemistry. posttranslational modifications (PTMs) on proteins Raj is also interested in identifying lysine methylation with various cargoes. The dysregulation of monomethyl posttranslational modifications (PTMs), imaging lysine PTMs has been linked to a variety of different enzymes responsible for these PTMs, and determining biological malfunctions, yet the chemical methods for their role in various signaling pathways. Raj’s work was selective detection of mono methyl lysine PTMs are recognized by several awards NSF CAREER award in still lacking. This selective tagging methodology can 2018, NIH MIRA award 2019, and Sloan Research effectively detect monomethyl lysine PTMs thus has a Award in 2020. Raj received several early career potential to further our understanding of the role of lectureship and rising star awards in chemical biology monomethylated lysine containing PTMs in regulating across the globe, including the American Peptide various cellular signaling processes.

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Session 5: Chemical Technologies to Promote Drug Discovery “Mapping Immune Cell Interactions via Dr. Rob Oslund Photocatalytic Proximity Labeling”

Membrane proteins play essential roles in an extensive range of cellular functions. One notable example is Associate Principal Scientist the surface interaction between immunomodulatory Merck Exploratory Science receptors (IMRs) to initiate and regulate immune Center, Merck & Co., Inc., responses. The success in modulating these Cambridge, Massachusetts, interactions with checkpoint inhibitors such as USA anti-PDL1/CTLA4 demonstrates the tremendous therapeutic value in understanding how IMRs interact Rob Oslund is originally from Las Vegas, Nevada and the impact of neighboring proteins on modulating and did his undergraduate studies at Southern Utah IMR function. Protein proximity labeling represents University. Rob obtained his PhD under Mike Gelb a powerful approach for the unbiased assessment of at the University of Washington and performed protein-protein interactions or bystander proteins postdoctoral studies with Tom Muir at Princeton with effector function on the cell surface. A number University. While at Princeton, Rob developed the of enzyme-based proximity labeling strategies have first pan-specific phosphohistidine antibodies and been developed over the last decade that either used them to explore hisitidine phosphorylation in generate a reactive labeling species in proximity to the bacterial signaling pathways and mammalian biology. protein of interest, or physically “stamp” neighboring He then moved to Neon Therapeutics and developed proteins. The success of these approaches has led to a proteomic-based technology to better understand the consideration of non-enzyme based methods that peptide presentation on HLA class I and II molecules are smaller in size, can be temporally controlled, and/ of therapeutic interest. Rob is currently a chemical or can avoid harsh treatment conditions. This talk biologist at the Merck Exploratory Science Center in will describe the development of novel photocatalytic- Cambridge, MA where he develops novel chemistry- based proximity labeling approaches whereby protein based technologies and applies them to explore residues are labeled in the presence of visible light and biological systems and enhance therapeutic discovery. a photocatalyst. Applications of this technology on the cell surface and within cell interaction environments will also be showcased.

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Session 5: Chemical Technologies to Promote Drug Discovery appointed as an Associate Editor for the Journal of the Dr. Phil Baran American Chemical Society. He co-founded Sirenas Marine Discovery (2012) and Vividion Therapeutics (2016) and in 2013 he co-authored The Portable Chemist’s Consultant, an interactive book published on the iBooks store along with his graduate class in Professor, The Scripps Research Institute Heterocyclic Chemistry (viewable on YouTube). The Baran laboratory is committed to identifying areas of chemical synthesis that can have a dramatic impact on the rate of drug discovery and development. This is achieved both through the development of practical total syntheses of complex natural products (such as Phil Baran was born in 1977 in Denville, New Jersey. terpenes, alkaloids, peptides, and oligonucleotides) He received his B.S. in chemistry from NYU in 1997, and by inventing reactions which can dramatically his Ph.D. The Scripps Research Institute in 2001, and simplify retrosynthesis. from 2001-2003 he was an NIH-postdoctoral fellow Outside of the lab, Phil enjoys spending time with his at Harvard. His independent career began at Scripps wife Ana and three young children (Lucia, Leah, and in the summer of 2003. Phil has published over 220 Manuel). scientific articles, several patents, and has been the recipient of several ACS awards such as the Corey (2015), Pure Chemistry (2010), Fresenius (2006), and Nobel Laureate Signature (2003), and several “Simplicity and Ideality in Synthesis” international distinctions such as the Hirata Gold Organic synthesis is one of the great branches of Medal and Mukaiyama Prize (Japan), the RSC award Chemistry that has had a profound impact on the in Synthesis (UK), the Sackler Prize (Israel), and the betterment and advancement of civilization. In its Janssen Prize (Belgium). In 2013 he was named a most modern manifestations, it renders the dream of MacArthur Foundation Fellow, in 2015 he was elected alchemy (turning something worthless into something to the American Academy of Arts and Sciences, in valuable) a reality. It places the practitioner into the 2016 he was awarded the Blavatnik National Award, role of artist, engineer, and astronaut. Thus, advances and in 2017, he was elected to the National Academy of in this field are inherently of interest to a broad Sciences, USA. He has delivered hundreds of lectures audience. Predicting the specific developments that around the world and consults for numerous companies will alter the course of this field is difficult. This talk such as Bristol-Myers Squibb, Gilead, Boehringer- will use case-studies from our lab to demonstrate how Ingelheim, AstraZeneca, DuPont and TEVA, and is the community is progressing by aiming for simple, a scientific advisory board member for Eisai, Abide, ideal solutions to longstanding challenges. Nutcracker, Quanta and AsymChem. In 2016 he was

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Session 6: Rising Stars To advance the career development of young investigators in chemical biology, ICBS has established a special session at the Annual Meeting to showcase up-and-coming chemical biology scientists. The selected recipients will give a presentation during the special “Rising Stars” session, and each will be further recognized for their achievements with a certificate and a monetary award. “Multicolor, high resolution, non-invasive Dr. Ellen Sletten imaging in mice”

Purpose: Multicolor, high-resolution experiments are ubiquitous in cellular imaging; however, analogous Assistant Professor studies in small animals are challenging due to John McTague Career background autofluorescence as well as absorption and Development Chair scattering of light by tissue. Our work allows for real- University of California, Los time multicolor in vivo imaging in mice, facilitating Angeles the extension of chemical biology tools to mammals.

Prof. Ellen Sletten received her BS in Chemistry from Methods: Our group develops new fluorophores Stonehill College in 2006. Ellen pursued her PhD in that emit in the SWIR region of the electromagnetic Chemistry at the University of California, Berkeley spectrum. We focus on polymethine dyes and modify with Prof. Carolyn Bertozzi. Her thesis work involved the heterocycles to tune the absorption, emission, the optimization and development of bioorthogonal absorption coefficient, quantum yield, and solubility chemistries and their subsequent applications in of the fluorophores. labeling living systems. Upon graduation in 2011, Ellen joined the laboratory of Prof. Tim Swager at Results: We have developed a series of bright flavylium the Massachusetts Institute of Technology as an NIH polymethine fluorophores that can be excited at Postdoctoral Fellow where she worked with soft orthogonal wavelengths throughout the near infrared fluorous materials for use in fluorescent sensors. Ellen (NIR, 700–1000 nm) and SWIR regions and produce joined the faculty in the Department of Chemistry and high resolution SWIR images in mice. The orthogonal Biochemistry at University of California, Los Angeles excitation allows for multiplexed experiments with up as an Assistant Professor and John McTague Career to four colors at video rate speeds. Using these bright Development Chair in 2015. Her group’s work develops SWIR contrast agents in conjunction with an excitation chemical tools to control and detect chemistries in multiplexing setup, we are able to probe vasculature living systems, with ultimate applications in enhanced dynamics and image awake animals. therapeutics and diagnostics. Ellen’s early career awards include an Alfred P. Sloan Fellow, NIH New Innovator Conclusion: We have demonstrated the first four, color, Award, Mercator Fellow, and Hellman Fellow. real-time non-invasive imaging in mice by employing a series of NIR and SWIR polymethine fluorophores for excitation multiplexed imaging.

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Rising Stars Session To advance the career development of young investigators in chemical biology, ICBS has established a special session at the Annual Meeting to showcase up-and-coming chemical biology scientists. The selected recipients will give a presentation during the special “Rising Stars” session, and each will be further recognized for their achievements with a certificate and a monetary award. “New insights into acetylation & Dr. Jordan L. Meier oncometabolism from chemoproteomics”

A paradox of modern biology is that while metabolism is known to influence epigenetic signals (including, Senior Investigator, but not limited to histone acetylation), the specific Chemical Biology Laboratory proteins that sense these metabolic cues remain Head, Epigenetics & uncharacterized. Here we describe the utility of chemical Metabolism Section methods to discover novel epigenetic mechanisms and National Cancer Insitute, USA characterize their metabolic regulation. Our initial studies have led to the identification of novel metabolic Dr. Meier received his undergraduate degree from inhibitors of histone acetyltransferases, an expanded Creighton University in 2004, getting introduced to understanding of RNA cytidine acetylation, and new chemistry research as an National Science Foundation signaling functions of the covalent oncometabolite REU student. Following graduation he moved to fumarate. Through our efforts, we aim to define novel the University of California-San Diego, performing biological pathways which influence the development, graduate research in under the mentorship of Professor progression, and treatment of cancer. Michael D. Burkart. After receiving his Ph.D. in 2009, he moved to Caltech to train as an American Cancer Society postdoctoral fellow in the laboratory of Professor Peter B. Dervan. In 2013, Dr. Meier joined the NCI, where his research focuses on the development of new methods to investigate metabolism-epigenetics interface in cancer.

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Rising Stars Session To advance the career development of young investigators in chemical biology, ICBS has established a special session at the Annual Meeting to showcase up-and-coming chemical biology scientists. The selected recipients will give a presentation during the special “Rising Stars” session, and each will be further recognized for their achievements with a certificate and a monetary award. “Precision control of CRISPR-associated Dr. Amit Choudhary nucleases”

CRISPR-associated nucleases (e.g., SpCas9, SaCas9, Cpf1) are programmable RNA-guided DNA Assistant Professor of Medicine, endonucleases that are furnishing “disruptive” Harvard Medical School technologies for basic research, biotechnology and medicine. SpCas9 allows facile induction of genomic alterations and the rapid spread of these alterations in a population via gene drives. Precision control lies at the heart of powerful technologies and CRISPR- Amit Choudhary is an Assistant Professor of Medicine based technologies are no exceptions. They require at Harvard Medical School. His doctoral research at multidimensional control over half-life, dosage, and the University of Wisconsin-Madison (Advisor: Prof. spatiotemporal as off-target effects, chromosomal Ronald Raines) elucidated a new molecular force translocations, immunogenicity, and genotoxicity are that is akin to the hydrogen bond in its function and observed at its elevated dose or prolonged activity. quantum mechanical origin. Subsequently, he was We have developed several CRISPR controllers appointed a Junior Fellow of the Harvard Society (activators, inhibitors, and degraders) and precision of Fellows (Host: Prof. Stuart Schreiber), where he enhancers to elevate these technologies to their fullest worked on beta cell biology. His laboratory develops potential, pivoting on specific applications in beta-cell chemical technologies inspired by specific problems in engineering. beta cell biology. His group’s effort has been recognized We anticipate our controllers and precision enhancers by Burroughs Wellcome Fund’s career award, NIH will find widespread use in basic, biomedical, and Director’s Transformative Research Award, DARPA’s defense research, as well as in therapeutic settings. Safe Genes award, and Vilcek Prize.

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Rising Stars Session To advance the career development of young investigators in chemical biology, ICBS has established a special session at the Annual Meeting to showcase up-and-coming chemical biology scientists. The selected recipients will give a presentation during the special “Rising Stars” session, and each will be further recognized for their achievements with a certificate and a monetary award. “Translational Site-Selective Antibody Dr. Gonçalo Bernardes Modification”

Our research uses chemistry principles to address questions of importance in life sciences and molecular Reader in Chemical Biology, Department of Chemistry, medicine. This lecture will cover recent examples of University of Cambridge, UK & reaction engineering for site-selective modification Instituto de Medicina of proteins and antibodies, and their use for targeted Molecular, Lisbon, Portugal therapeutics.

After completing his D.Phil. in 2008 at the University of Oxford, U.K., he undertook postdoctoral work at the Max-Planck Institute of Colloids and Interfaces, Germany, and the ETH Zürich, Switzerland, and worked as a Group Leader at Alfama Lda in Portugal. He started his independent research career in 2013 at the University of Cambridge as a Royal Society University Research Fellow. In 2018 he was appointed University Lecturer (Tenured) and recently has been promoted to Reader (Associate Professor). Gonçalo is the recipient of two European Research Council grants; a starting grant and a proof-of-concept grant, and was awarded the Harrison–Meldola Memorial Prize in 2016 and the MedChemComm Emerging Investigator Lectureship in 2018, both from the Royal Society of Chemistry. His research group interests focus on the use of chemistry principles to tackle challenging biological problems for understanding and fight cancer.

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Opening Day Trainee Forum Maria L. Adrover-Castellano1, Jennifer J. Schmidt2, and David H. Sherman3

1Life Sciences Institute and Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States 2Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States 3Life Sciences Institute, Department of Medicinal Chemistry, Program in Chemical Biology, Department of Chemistry, and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan 48109, United States

“Thioesterase directed evolution approach for yield improvement and expansion of the substrate scope to generate macrolactones” Type I modular polyketide synthases (PKSs) are a family of enzymes capable of synthesizing a diverse class of natural products, which form the basis for approximately one-third of pharmaceuticals. The biochemical features of these systems include the extension and processing of polyketide chains in a stepwise, stereospecific manner, organized by a series of catalytic domains divided into distinct modules. Taking advantage of these enzymes as biocatalysts would be a powerful addition to the synthetic chemistry toolbox that allow for a more sustainable and environmentally responsible approach to molecular diversification. Previous work by the Sherman Lab, has indicated that the primary hurdle to utilizing PKS modules to produce diverse macrolactones hinges on the selectivity of the thioesterase (TE). Recently, we have demonstrated the ability to form 12-membered rings utilizing an amide hexaketide in conjunction with an engineered TE S148C from the pikromycin biosynthetic pathway. Despite this success, these 12-membered rings were formed in significantly attenuated yields in comparison with the native substrate mostly due to linear hydrolytic byproducts. Utilizing these initial results, we proposed to embark on a directed evolution campaign to identify TE’s with enhanced selectivity for the desired 12-membered rings. This project focuses on merging synthetic chemistry and protein engineering to expand the use of PKS TEs (in conjunction with their upstream modules) as biocatalysts to produce structurally complex polyketide macrocycles. Our study will give critical insights into the amino acid residues that impart improved selectivity and yield with these substrates, which have broader applications to additional substrates as well as future engineering efforts in the pursuit of combinatorial strategies to produce these synthetically challenging molecules.

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Opening Day Trainee Forum Lan Jiang1, †, Guoliang Zhu1, †, Xue Zhang1, Weiyan Zhang1, Kangjie Lv1, Huanqin Dai2, Chengjian Hou1, Shuliu Wang1, Zhanren Cong1, Xinye Wang1, Xiangying Chen1, Jiakun Liu3, Zhixin Wang1, Jingyu Zhang1, Huanting Yang1, Tong Xie1, Gaoyi Tan1, Guang Liu1, Chengwei Liu4, Hideaki Oikawa5, Tom Hsiang6, Xueting Liu1,*, and Lixin Zhang1,*

1State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. 2Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. 3CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences, Shenzhen 518000, China. 4Key Laboratory of Saline-alkali Vegetation Ecology Restoration, Ministry of Edu- cation, Northeast Forestry University, Heilongjiang 150040, China. 5Division of Chemistry, Graduate School of Science, Hokkaido University, Sap- poro 060-0810, Japan. 6School of Environmental Sciences, University of Guelph, Ontario N1G 2W1, Canada. †Contributed equally to this work. “Fungal multi-functional cytochrome-P450 responsible for the biosynthesis of unprecedented BFTS-related norditerpenoids” The chemical diversity of terpenoids is typically established by terpene synthase-catalyzed cyclization and diversified post-tailoring modifications. In this study, we discovered 7 norditerpenoids (19 carbons) with an extremely structurally unique 5-5 bicyclic ring system upon heterologous expression of two enzymes, the fungal bifunctional terpene synthase (BFTS) and the cytochrome P450 enzyme, from the phytopathogenic fungus Didymosphaeria variabile 17020 (DV17020). Interestingly, our data support that the expression of a single P450 enzyme VndE in Aspergillus oryzae NSAR1 cells results in formation of all 7 of these norditerpenoids. This findings suggests that, perhaps similar to the highly unique Fma-P450 of fumagillin biosynthesis, VndE apparently functions in multiple enzymatic reaction types at multiple substrate carbon positions (e.g. C-6, C-7, and C-10). Our work reveals a compact, two-enzyme biosynthetic system that can produce structurally unique terpenoids from an unprecedented skeleton and showcases the extremely flexible catalytic capacities of fungal P450 enzymes.

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Opening Day Trainee Forum Hyungyu Lee, Danielle Dube*

*Department of Chemistry & Biochemistry, Bowdoin College, 6600 College Station, Brunswick, ME 04011 (USA)

“Comparison of Covalent Delivery Methods and Their Effects for Immune- mediated Killing of Helicobacter pylori” Helicobacter pylori is gram-negative bacteria that infects almost 50% of the world’s population. It is a pathogenic agent that is responsible for causing duodenal ulcers, gastritis, and even gastric cancer. Due to the rise in antibiotic resistant bacteria, triple therapy with a combination of two antibiotics and a proton pump inhibitor is becoming ineffective at clearing H. pylori infection. In order to effectively cure H. pylori infection, a new therapeutic methodology must be developed. Bacterial glycans are an attractive target for new treatments as they are linked to pathogenesis and contain unique structures that are absent in human. This project explores the utility of Metabolic Oligosaccharide Engineering as a means to surface glycans of H. pylori with azides and target them with a bioorthogonal reaction partner bearing the immune-stimulant 2,4-dinitrophenyl to induce immune- mediated damage. In particular, three different methodologies were compared for covalent delivery of the DNP epitope to azide-coated H. pylori: Staudinger ligation with a phosphine-based reactive partner, strain promoted azide-alkyne cycloaddition with a dibenzoazacyclooctyne-based reactive partner, and copper catalyzed azide- alkyne cycloaddition with an alkyne-based reactive partner. The effect of immune-mediated killing associated with each delivery method will be presented.

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Opening Day Trainee Forum Beverly Y. Mok†1,2,3, Marcos H. de Moraes4,†, Jun Zeng4, Dustin E. Bosch4,5, Anna V. Kotrys8,9,10, Aditya Raguram1,2,3, FoSheng Hsu4, Matthew C. Radey4, S. Brook Peterson4, Vamsi K. Mootha8,9, Joseph D. Mougous4,6,7* and David R. Liu1,2,3* 1Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA 2Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA 3Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts, USA 4Department of Microbiology, University of Washington School of Medicine, Seattle, USA 5Department of Pathology, University of Washington School of Medicine, Seattle, USA 6Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, USA 7Howard Hughes Medical Institute, University of Washington, Seattle, USA 8Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA 9Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA 10Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland † Authors contributed equally * To whom correspondence should be addressed: [email protected], [email protected]

“A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing” Bacterial toxins represent a vast reservoir of biochemical diversity that can be repurposed for biomedical applications. Here, we report the discovery of DddA, an interbacterial toxin that catalyzes the unprecedented deamination of cytidines within double-stranded DNA (dsDNA). All previously described cytidine deaminases operate on single-stranded DNA and thus when applied to genome editing require unwinding of dsDNA by macromolecules such as CRISPR-Cas9 complexed with a guide RNA1,2. Challenges associated with guide RNA delivery into the mitochondria have thus far precluded base editing within mitochondrial DNA (mtDNA)3. We reasoned that the ability of DddA to act on dsDNA could circumvent this barrier. Using DddA, we developed a CRISPR-free DddA-derived cytosine base editor (DdCBE) that catalyzes C•G-to-T•A conversions in human mtDNA with high DNA sequence specificity and product purity, resulting in changes in mitochondrial function. DdCBEs enable precise manipulation of mtDNA, rather than the elimination of mtDNA copies that results from mtDNA cleavage, with important basic science and biomedical implications.

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Opening Day Trainee Forum Pragya Jatoo1, Alexander Wolf1, Carsten Janke2, Bert Klebl1

1Lead Discovery Center, Germany, 2Institute Curie, Orsay, France

“A Chemical Biology approach to decipher the Tubulin Code” Glutamylation is a Post Translational Modification (PTM) that results in addition of secondary glutamate side chains in an ATP dependent reaction. In eukaryotes, this PTM is carried out by the Tubulin Tyrosine Ligase Like (TTLL) family Glutamylases. Arguably, one of the most important substrates of TTLLs are the Microtubules (MT). This PTM is known to dictate the function and even the dynamics of MTs- in a graded fashion. Hyperglutamylation on MTs has been linked to neuronal defects but the underlying mechanisms are largely unknown. Glutamylation is one of the many PTMs that the MTs are subject to. This mechanism of modulation of MT properties and functions by a “PTM signal map” is called the Tubulin Code. This study aims to identify small molecules that selectively inhibit the activity of TTLL Glutamylases. These inhibitors can be used as chemical tools to study the role of this PTM in regulating MT behavior and to develop a deeper understanding of the molecular mechanisms underlying hyperglutamylation associated pathologies. Identified substances can also serve as future drug precursors. To this end, a small molecule library consisting of approximately 188,000 compounds was screened against TTLLx in a high throughput fashion for which a novel primary assay was developed. 721 primary hits obtained from the High Throughput Screening (HTS) were verified by orthogonal assays. We report the identification of validated biochemical inhibitors of TTLLx. These are being currently characterized in cell based and other mechanistic assays. Barring the reaction analogs, there are presently no known inhibitors of TTLLs. This is the first HTS campaign against the TTLLs. Identification of these inhibitors is my PhD project that I am carrying out at the Lead Discovery Center (LDC) in Dortmund, Germany in close collaboration with Max Planck Institute for Molecular Physiology, Dortmund and Institut Curie, France. LDC specializes in early drug discovery and functions at the interface of academia and industry hence uniquely bridging the translational gap.

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Opening Day Trainee Forum Matthew Worth1, Chia-Wei Hu2, Hao Li2, Dacheng Fan2, Arielis Estevez2, Dongsheng Zhu2, Ao Wang2 and Jiaoyang Jiang2 1Department of Chemistry, University of Wisconsin–Madison, Madison, Wisconsin 53705, USA. 2Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin– Madison, Madison, Wisconsin 53705, USA.

“Targeted covalent inhibition of O-GlcNAc transferase in cells” O-GlcNAc transferase (OGT) glycosylates numerous proteins and is implicated in many diseases. To date, most OGT inhibitors lack either sufficient potency or characterized specificity in cells. We report the first targeted covalent inhibitor that predominantly reacts with OGT but does not affect other functionally similar enzymes. This study provides a new strategy to interrogate cellular OGT functions and to investigate other glycosyltransferases.

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Opening Day Trainee Forum Shwetha Srinivasan1, Raju Regmi1, Xingcheng Lin1, Courtney A. Dreyer2, Steven Quinn1, Xuyan Chen1, Wei He4, Kermit L. Carraway, III2, Matthew A. Coleman3,4, Bin Zhang1, Gabriela S. Schlau-Cohen1 1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, United States 2Biochemistry and Molecular Medicine, 3Radiation Oncology, University of California Davis School of Medicine, Sacramento, California, United States 4Lawrence Livermore National Laboratory, Livermore, California, United States

“Conformational coupling across the membrane bilayer of Epidermal Growth Factor Receptor” Membrane proteins, the cellular gatekeepers have been implicated in a myriad of cellular processes ranging from gene expression to cell differentiation and apoptosis. These systems constitute nearly 30% of the human proteome and about 60% of the current pharmaceutical drug targets. Membrane receptors, a class of membrane proteins, transduce signal between the cell and its external environment. One such key receptor is the epidermal growth factor receptor (EGFR). EGFR is a canonical example of a receptor tyrosine kinase and plays a crucial signaling role in key cellular functions including, but not limited to, cell proliferation, differentiation and survival. Overexpression or mutations in EGFR cause several diseases including cancer. While the structures of the extracellular and intracellular regions, in parts, of this protein have been well elucidated, conformational coupling connecting these two regions during the signal transduction is poorly understood and challenging to probe. In this talk, I will discuss the signal transduction mechanism across full-length EGFR. We combine two biochemical tools, cell-free expression and nanodiscs, to isolate full-length, functional EGFR in a near-physiological environment. We explore the conformational changes in the intracellular domain of EGFR upon extracellular ligand and drug binding using a multidisciplinary approach involving single-molecule Förster resonance energy transfer, mutagenesis and molecular dynamics simulations. Furthermore, we probe the effect of the composition of the lipid environment, which can be optimally tuned using cell-free expression and nanodiscs, in the signal transduction mechanism of EGFR. The findings have implications in understanding communication between the cell and its environment via this crucial receptor.

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Opening Day Trainee Forum Elisabeth Hennes, Slava Ziegler and Herbert Waldmann* Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany

“Detection of Modulators of the Kynurenine Pathway in Cells” To date, various mechanisms on how cancer cells escape from immune cell-mediated elimination have been elucidated and open up new possibilities for targeted cancer immunotherapy. The activity of the kynurenine pathway (KP) and its rate limiting enzyme indolamine 2,3-dioxygenase (IDO1) are essential for maintaining immune- privileged sites but also to strengthen cancer immune escape. And overexpression of the immunoregulatory enzyme IDO1 have been found in various cancers. IDO1 catalyzes the conversion of the essential amino acid tryptophan (Trp) to N-formylkynurenine that is further degraded along the KP to the stable metabolite kynurenine (Kyn). The depletion of Trp and the accumulation of Kyn suppress the immune system through inhibition of effector tumor-infiltrating immune cells, promotes regulatory T cells, thus, facilitating cancer cell progression. Hence, downregulation of the kynurenine pathway in cancer could support immune-mediated elimination of cancer cells. To identify small molecule modulators of the KP we developed a phenotypic assay applicable for high- throughput screening to monitor kynurenine production in cancer cells. The screening of a library of 157,332 compounds identified highly potent compound classes of different chemotypes that reduce kynurenine levels with different mode of action.

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Opening Day Trainee Forum Dhanushka N. P. Munkanatta Godage1,2, Sachini U. Siriwardena1,2, Veron- ika M. Shoba1,2, Sophia Lai1,3, Mengchao Shi12,4, Peng Wu1,2,4, Santosh K. Chaudhary1,2, Stuart L. Schreiber1,3, and Amit Choudhary1,2,4 1Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 2Department of Medicine, Harvard Medical School, Boston, MA 02115, USA 3Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA 4Divisions of Renal Medicine and Engineering, Brigham and Women’s Hospital, Boston, MA 02115, USA

“Phosphorylation-Inducing Chimeric Small Molecules” Several new classes of small molecules are emerging that endow new functions to enzymes via proximity-mediated effects. Protein phosphorylation profoundly influences their structures and functions, and kinase inhibitors have had a transformative impact on basic science and medicine. We hypothesize that small molecules that induce phosphorylation of any given protein-of-interest on-demand will also be useful in many scenarios. For example, such molecules can be used to trigger cell-signaling events or neo-phosphorylations that are not observed in a native cellular environment. Neo-phosphorylation can alter protein structure and function, evoke an immune response, or affect the protein’s interaction with other biomolecules, particularly with RNA/DNA that have negatively-charged phosphodiester backbone. Installing phosphoryl groups on Ser/Thr residues will block other posttranslational modifications, including O-GlcNAcylation. We describe a new class of bifunctional molecules termed phosphorylation-inducing chimeric small molecules (PHICS) formed by linking a kinase binder with a small-molecule binder of the target protein (J. Am. Chem. Soc. 2020, 142, 14052). Using PHICS and AMP-activated protein kinase (AMPK) or protein kinase C (PKC), we have induced phosphorylation of BRD4, BTK, FKBP12 and ABL. Furthermore, PHICS induced a signaling-relevant phosphorylation of the target protein Bruton’s tyrosine kinase (BTK) in cells. PHICS exhibited the hallmarks of a typical bifunctional molecule, including the hook effect, turnover, dependence on linker, isoform specificity, and dose- and temporal-control of phosphorylation. Beyond these studies, we have generated PHICS to affect tyrosine phosphorylation and developed kinase binders that induce phosphorylation at different stoichiometries on the target protein. Finally, we have developed a chemogenetic system consisting of an engineered kinase that can be recruited by PHICS, enabling rapid evaluation of the biological effects of neo-phosphorylation. We envision that PHICS-mediated native- or neo-phosphorylations will find utility in basic research and medicine.

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Opening Day Trainee Forum Career Talk & Panel Discussion Panelists

Dr. Colleen Keohane Scientist, Discovery Chemistry Janssen: Pharmaceutical Companies of Johnson & Johnson

Dr. Luca Laraia Assistant professor at DTU in Denmark Chemical biology of processes governed or controlled by sterols

Dr. Kathryn Hosbein Postdoctoral associate at University of Michigan Chemistry Education Researcher

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Presenter Index A L Maria L. Adrover-Castellano...... 41 Luca Laraia...... 50 Douglas S. Auld...... 26 Gabsang Lee...... 21 Hyungyu Lee...... 43 B Nir London...... 32 Keriann Backus...... 16 M Phil Baran...... 36 Gonçalo Bernardes...... 17, 40 Jordan L. Meier...... 38 James (Jay) Bradner...... 12 Beverly Y. Mok...... 44 Dhanushka N. P. Munkanatta Godage...... 49 C N Justin Chalker...... 18 Shuibing Chen...... 19 Daniel K. Nomura...... 27 Amit Choudhary...... 39 O D Rob Oslund...... 35 Danette Daniels...... 30 Manuel de Lera Ruiz...... 25 R F Monika Raj...... 34 Hans Renata...... 33 Dacheng Fan...... 46 Matthew Robers...... 24 G S Adam Gilbert...... 29 Alanna Schepartz...... 13 Nigel H. Greig...... 20 Stuart Schreiber...... 14 Zijian Guo...... 10 Ellen Sletten...... 37 Mikiko Sodeoka...... 11 H Shwetha Srinivasan...... 47 Elisabeth Hennes...... 48 W Kathryn Hosbein...... 50 Herbert Waldmann...... 15 J Zhexing Wen...... 22 Pragya Jatoo...... 45 Tim Willson...... 23 Lan Jiang...... 42 Georg Winter...... 31 K Z Colleen Keohane...... 50 Andrew Zhang...... 28

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Thank you to our conference sponsors

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