Angela N. Koehler

Koch Institute for Integrative Cancer Research at MIT Office: 617-324-7631 Department of Biological Engineering, MIT Email: [email protected] 76-361C Website: http://koehler-lab.mit.edu/ 77 Massachusetts Avenue Cambridge, MA 02139

Education

Ph.D. Chemistry, Harvard University 2003 B.A. and Molecular Biology, Reed College 1997

Professional Appointments

Associate Professor, Department of Biological Engineering, MIT 2019-present Institute Member, Broad Institute of MIT and Harvard 2019-present Founding Member, MIT Center for Precision Cancer 2018-present Goldblith Career Development Professor in Applied Biology 2018-2021 Intramural Faculty, Koch Institute for Integrative Cancer Research at MIT 2014-present Assistant Professor, Department of Biological Engineering, MIT 2014-2018 Karl Van Tassel (1925) Career Development Professor 2014-2017

Director, Transcriptional , Chemical Biology Program, Broad Institute 2010-2013 Project & Center Manager, Broad NCI Cancer Target Discovery and Development (CTD2) Center Institute Fellow, Chemical Biology Program, Broad Institute 2003-2009 Director, Ligand Discovery, NCI Initiative for Chemical (ICG) at Harvard

Research Training

Graduate Student, Department of Chemistry and Chemical Biology, Harvard University 1998-2003 Laboratory of Professor Stuart L. Schreiber Committee: Professors Eric. N. Jacobsen, David R. Liu Thesis: Small molecule microarrays: A high-throughput tool for discovering protein-small molecule interactions

Researcher, Department of Chemistry, California Institute of Technology 1997-1998 Laboratory of Professor Barbara Imperiali Project: Biochemical reconstitution of the oligosaccharyltransferase (OST) complex

Undergraduate Researcher, Department of Chemistry, Reed College 1995-1997 Laboratory of Professor Arthur Glasfeld Co-mentored by Professor Richard G. Brennan at Oregon Health Sciences University Thesis: Biochemical and structural characterization of the tRNA-modifying enzyme QueA from Escherichia coli

Teaching

Massachusetts Institute of Technology Analysis of Biomolecular and Cellular Systems (20.320) F14, F15 Biological Engineering Design (20.380) S15, S16, F16, F17 Laboratory Fundamentals in Biological Engineering (20.109) S17, S18, S19, F19, S20

Harvard University Biochemical Sciences Research for Undergraduates (BS91r) 2004-present Experimental Research in the Life Sciences (LS100r) F09 Experimental Molecular and Cellular Biology (MCB100) F04, S05, F05, S06

Honors and Awards

Junior Bose Award for Teaching Excellence, MIT 2019 NSF CAREER Award 2019 AACR-Bayer Innovation and Discovery Award 2018 Ono Foundation Pharma Breakthrough Award 2017 Novartis Lectureship in Chemistry 2017-2018 Merkin Institute Fellow, Broad Institute, MIT 2014 Genome Technology Young Investigator 2012-2013 Kavli Frontiers of Science Scholar, US National Academy of Sciences 2011 Indo-US Frontiers of Science Exchange Award 2011 Eli Lilly Predoctoral Fellowship in Organic Chemistry, Harvard University 2001-2002 MIT 50K Entrepreneur Team Competition, Finalist 2001 Excellence in Scholarship Award, Reed College 1995-1997 William and Jane Einzig Memorial Scholarship, Reed College 1993-1997 ESCO Undergraduate Scholarship, Reed College 1993-1997

Professional Service

ACS Pharmacology & Translational Science Editorial Advisory Board 2019-present Cell Reports Physical Science Editorial Advisory Board 2019-present Co-Director, MIT Biomedical Engineering Minor Program, Department of Biological Engineering 2017-present Steering Committee, Cancer Program, Broad Institute 2017-present Committee on Pre-Health Advising (COPA), MIT Global Education & Career Development Office 2016-present 2018 AACR Annual Meeting Program Committee, Chairperson of the Proteomics and Mass 2017-2018 Spectrometry Section of the Cancer Chemistry Subcommittee Koch Institute/Biology Department Faculty Search Committee 2017-2018, 2019-2020 Chair, 2017 BE Retreat Organizing Committee 2017 MIT Deshpande Center Finalist Review Panel 2017 Chemistry in Cancer Research Steering Committee, American Association for Cancer Research 2016-2018 Faculty Advisor, Biological Engineering Resources for Easing Friction and Stress (REFS) 2016-2018 MIT Biological Engineering, Communications Lab Hiring Committee 2016-2017 Faculty Co-advisor, High-Throughput Screening Facility, Koch’s Swanson Biotechnology Center 2014-present MIT Biological Engineering Graduate Program Committee 2014-present MIT Biological Engineering Faculty Recruitment Committee 2014-2015 Ad Hoc Reviewer, Chemistry of Life Sciences, National Science Foundation 2014 Florida Translational Research Program, Sanford-Burnham, External Advisory Panel 2013-2015 Broad@10 Therapeutics Council, Broad Institute 2013-2014 Broad@10 Leadership and Connectivity Committee, Broad Institute 2013-2014 Standing Member, NIH Drug Discovery and Molecular Pharmacology (DMP) Study Section 2013-2020 MISTI Global Seeds Fund Review Panel, MIT 2013 Lawrence H. Summers Fellowship Selection Committee, Broad Institute 2012 Ad Hoc Member, NIH Drug Discovery and Molecular Pharmacology (DMP) Study Section 2012 Science of Therapeutics (SofT) Organizing Committee, (Chair, 2013-2014), Broad Institute 2011-2014 Dana-Farber Cancer Institute CURE Program for URMs 2011, 2013 Ad Hoc Member, NIH Synthetic and Biological Chemistry B (SBCB) Study Section 2011 Principal Advisor, STEMid, Harvard and MIT 2011-2013 Chemical Biology Program Leadership Committee, Broad Institute 2010-2013 Advisory Panel, NRC Canada, Genomics and Health Initiative, BioChips Project 2008-2011 Broad Institute Summer Research Program in Genomics for URMs 2007-2012 Broad Institute Educational Outreach Program Admissions Panel and Research Mentor 2007-2012 Intel National Science Talent Search Mentor (Megan Blewett, 7th-place out of 1,700) 2006-2007 High-Throughput Screening Review Board, Broad Institute 2005-2012 Chembank Steering Committee, NCI Initiative for Chemical Genetics 2005-2006 Technology Platform Committee, Broad Institute 2004-2006

Industry Relationships

Scientific Collaboration, MIT-GSK G.B. Elion Fellowship (Struntz, Koehler) 2018-present Scientific Founder, Scientific Advisory Board Member, Consultant, Kronos Bio, Cambridge, MA. 2017-present Consultant, Proteostasis, Cambridge, MA 2017 Consultant, Novartis, Oncology, Cambridge, MA 2016-2018 Scientific Advisory Board Member, MS2Array, Pittsburgh, PA. 2015-present Scientific Collaboration, Transcend Program, Janssen Pharmaceuticals 2014-2016 Scientific Founder, Consultant, Ligon Discovery, Cambridge, MA 2007-2011

Publications

Department of Biological Engineering, Koch Institute for Integrative Cancer Research, MIT

1. Andrew Chen, Angela N. Koehler, Inhibiting transcription factors: lessons learned and emerging targets.” Trends in Molecular Medicine, Submitted, October 2019. 2. Nicholas B. Struntz, Andrew Chen, Anja Deutzmann, Robert M. Wilson, Eric Stefan, Helen L. Evans, Maricela A. Ramirez, Tong Liang, Francisco Caballero, Mattheus H. Wildschut, Dylan V. Neel, Marius S. Pop, Marie McConkey, Sandrine Muller, Brice H. Curtin, Hanna Tseng, Kristen R. Frombach, David B. Freeman, Vincent L. Butty, Stuart S. Levine, Clementine Feau, Sarah Elmiligy, Jiyoung A. Hong, Timothy A. Lewis, Amedeo Vetere, Paul A. Clemons, Scott A. Malstrom, Benjamin L. Ebert, Charles Y. Lin, Dean W. Felsher, Angela N. Koehler, “Stabilization of the Max homodimer with a small molecule attenuates Myc- driven transcription.” Cell Chemical Biology, 26, 711-723, 2019. 3. Becky S. Leifer, Shelby K. Doyle, Helen L. Evans, André Richters, Angela N. Koehler, “An array-based ligand discovery platform for proteins with short half-lives.” Methods in Enzymology, 610, 191-218, 2018. 4. David B. Freeman, André Richters, Marius S. Pop, Nicholas B. Struntz, Angela N. Koehler. “Emerging non- canonical small molecule inhibitors of Androgen Receptor (AR) and its interactome partners for the treatment of castrate-resistant prostate cancer.” Medicinal Chemistry Reviews, Volume 3, Chapter 14, 268-282, 2018. 5. André Richters, Angela N. Koehler, “Epigenetic Modulation using Small Molecules – Targeting histone acetyltransferases in disease, Current Medicinal Chemistry, 24, 4121-4150, 2017. 6. Jeffrey J. Coleman, Tomomi Kimura, Julia Munro, Michael P. Wu, Rakhee R. Busanelli, Angela N. Koehler, Meryl Thomas, Florence F. Wagner, Edward B. Holson, Eleftherios Mylonakis. “The Immunomodulatory activity of caffeic acid phenethyl ester in Caenorhabditis elegans is mediated by the CED-10 (Rac-1)/PAK-1 pathway.” Future Med. Chem., 8, 17, 2016. 7. Yikai Wang, Jean-Yves Wach, Patrick Sheehan, Cheng Zhong, Chenyang Zhan, Richard Harris, Steven C. Almo, Joshua Bishop, Stephen H. Haggarty, Alexander Ramek, Kayla Berry, Conor O’Herin, Angela N. Koehler, Alvin Hung, Damian W. Young. “Application of diversity-oriented synthesis as a strategy for fragment evolution against GSK3beta. ACS Med. Chem. Lett. 7, 852-856, 2016. 8. Zhihong Yang, Angela N. Koehler, Li Wang. “A novel small molecule activator of nuclear receptor SHP inhibits HCC cell migration via suppressing Ccl2.” Mol. Cancer Ther. 15, 2294-2301, 2016. 9. Zarko Boskovic, Melissa M. Kemp, Allyson M. Freedy, Vasanthi S. Viswanathan, Marius S. Pop, Jason H. Fuller, Nicole Martinez, Samuel O. Figueroa Lazu, Jiyoung A. Hong, Timothy A. Lewis, Daniel Calarese, James D. Love, Amedeo Vetere, Steven C. Almo, Stuart L. Schreiber, Angela N. Koehler. “A chemically triggered electrophile shows selective in vitro inhibition among zinc-dependent lysine deacetylases.” ACS Chem Biol. 11, 1844-1851, 2016. 10. Luc de Waal, Timothy A. Lewis, Matthew G. Rees, Aviad Tsherniak, Peter S. Choi, Lara Gechijian, Christina Hartigan, Patrick W. Faloon, Mark J. Hickey, Nicola Tolliday, Steven A. Carr, Paul A. Clemons, Benito Munoz, Bridget K. Wagner, Alykhan F. Shamji, Angela N. Koehler, Monica Schenone, Alex B. Burgin, Stuart L. Schreiber, Heidi Greulich, Matthew L. Meyerson. “Identification of cancer-cytotoxic modulators of phosphodiesterase 3a by predictive chemogenomics.” Nature Chemical Biology, 12,102-8, 2016. 11. Shelby K. Doyle, Marius S. Pop, Helen L. Evans, Angela N. Koehler, Advances in Discovering Small Molecules to Probe Protein Function in a Systems Context.” Curr. Opin. Chem. Biol. 30:28-36, 2016. 12. Zhengjian Zhang, Zarko Boskovic, Mahmud M. Hussain, Wenxin Hu, Carla Inouye, Han-Je Kim, Anna K. Abole, Mary K. Doud, Timothy A. Lewis, Angela N. Koehler, Stuart L. Schreiber, Robert Tjian, “Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation.” Accepted, eLife. 10.7554/eLife.07777, 2015. 13. Andrew Chen, Angela N. Koehler, “Tying up a transcription factor: Engineered bivalent small molecule inhibits CBFβ-SMMHC activity in leukemia subtype.” Science. 347, 713-714, 2015. 14. Marius S. Pop, Dina Wassaf, Angela N. Koehler, “Probing small molecule microarrays with tagged proteins in cell lysates.” Curr. Protoc. Chem. Biol. 6, 209-220, 2014. 15. Masoud Sadaghiani, Sang Min Lee, Justin I. Odegaard, Dennis B. Leveson-Gower, Olivia M. McPherson, Paul Novick, Mi Ri Kim, Angela N. Koehler, Robert Negrin, Ricardo E. Dolmetsch, Chan Young Park. "Identification of Orai1 channel inhibitors by using minimal functional domains to screen small molecule microarrays." Chem. Biol. 21, 1278-1292, 2014. 16. Marius S. Pop, Nicolas Stransky, Colin W. Garvie, Jean-Philippe Theurillat, Timothy A. Lewis, Cheng Zhong, Elizabeth K. Culyba, Fallon Lin, Doug S. Daniels, Raymond Pagliarini, Lucienne Ronco, Angela N. Koehler, Levi. A. Garraway. “A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein.” Mol. Cancer Ther. 6, 1492-1502, 2014. 17. Jiyoung A. Hong, Dylan V. Neel, Dina Wassaf, Francisco Caballero, Angela N. Koehler, “Recent discoveries and applications involving small-molecule microarrays.” Curr. Opin. Chem. Biol. 18, 21-28, 2014.

Broad Institute of Harvard and MIT, Institute Felllow

18. Izhack Cherny, Maria Korolev, Angela N. Koehler, Michael H. Hecht. “Proteins from an unevolved library of de novo designed sequences bind a range of small molecules.” ACS Synth. Biol., 1, 130-138, 2012. 19. Melissa M. Kemp, Michel Weïwer, Angela N. Koehler. “Unbiased binding assays for discovering small- molecule probes and drugs.” Bioorg. Med. Chem., 20, 1979-1989, 2012. 20. Dominick E. Casalena, Dina Wassaf, Angela N. Koehler. “Ligand discovery using small-molecule microarrays.” Chapter, Methods Mol. Biol., 803, 249-263, 2012. 21. Melissa M. Kemp, Qiu Wang, Jason H. Fuller, Nathan West, Nicole Martinez, Elizabeth M. Morse, Michel Weïwer, Stuart L. Schreiber, James E. Bradner, Angela N. Koehler, “A novel HDAC inhibitor with a hydroxy- pyrimidine scaffold.” Bioorg. Med. Chem. Lett., 21, 4164-4169, 2011. 22. Paul A. Clemons, J. Anthony Wilson, Vlado Dancik, Sandrine Muller, Hyman A. Carrinski, Bridget K. Wagner, Angela N. Koehler, Stuart L. Schreiber. “Quantifying structural property distributions and patterns of performance among sets of small molecules comprising small-molecule screening collections.” Proc. Natl. Acad. Sci. USA, 108, 6817-6822, 2011. 23. Myung-Soo Kang, Eun Kyung Lee, Vishal Soni, Timothy A. Lewis, Angela N. Koehler, Viswanathan Srinivasana, Elliott Kieff. ‘Roscovitine inhibits EBNA1 Serine 393 phosphorylation, nuclear localization, transcription, and episome maintenance.” J. Virol. 85, 2859-2868, 2011. 24. Jermont M. Chen, Anne H. Armstrong, Angela N. Koehler, Michael H. Hecht. “Small-molecule microarrays enable the discovery of compounds that bind the Alzheimer’s Ab peptide and reduce its cytotoxicity.” J. Am. Chem. Soc., 132, 17015-17022, 2010. This article was featured in the Research Highlights section of Nature Chemistry, November 26, 2010. 25. Paul A. Clemons, Nicole E. Bodycombe, Hyman A. Carrinski, J. Anthony Wilson, Alykhan F. Shamji. Bridget K. Wagner, Angela N. Koehler, Stuart L. Schreiber. “Small molecules of different synthetic and natural origins have distinct distributions of structural complexity that correlate with protein-binding profiles.” Proc. Natl. Acad. Sci. USA, 107, 18787-18792, 2010. 26. The Cancer Target Discovery and Development Network: Stuart L. Schreiber, Alykhan F. Shamji, Paul A. Clemons, Cindy Hon, Angela N. Koehler, Benito Munoz, Michelle Palmer, Andrew M. Stern, Bridget K. Wagner, Scott Powers, Scott W. Lowe, Xuecui Guo, Alex Krasnitz, Eric T. Sawey, Raffaella Sordella, Lincoln Stein, Lloyd C. Trotman, Andrea Califano, Riccardo Dalla-Favera, Adolfo Ferrando, Antonio Iavarone, Laura Pasqualucci, José Silva, Brent R. Stockwell, William C. Hahn, Lynda Chin, Ronald A. DePinho, Jesse S. Boehm, Shuba Gopal, Alan Huang, David E. Root, Barbara A. Weir, Daniela S. Gerhard, Jean Claude Zenklusen, Michael G. Roth, Michael A. White, John D. Minna, John B. MacMillan, Bruce A. Posner. “Towards patient-based cancer therapeutics.” Nature Biotechnology 28, 904-906, 2010. 27. Angela N. Koehler. “A complex task? Direct modulation of transcription factors with small molecules.” Curr. Opin. Chem. Biol. 14, Curr. Opin. Chem. Biol., 14, 331-340, 2010. 28. Arturo J. Vegas, Angela N. Koehler. “Detecting protein-small molecule interactions using fluorous small- molecule microarrays.” Methods Mol. Biol., 669, 43-55, 2010. 29. Carlos Tassa, Jay L. Duffner, Timothy A. Lewis, Ralph Weissleder, Stuart L. Schreiber, Angela N. Koehler, Stanley Y. Shaw. “Binding affinity and kinetic analysis of targeted small molecule-modified nanoparticles.” Bioconjugate Chemistry, 21, 14-19, 2010. 30. Benjamin Z. Stanton, Lee F. Peng, Nicole Maloof, Kazuo Nakai, Xiang Wang, Jay L. Duffner, Kennedy M. Taveras, Joel M. Hyman, Sam W. Lee, Angela N. Koehler, James K. Chen, Julia L. Fox, Anna Mandinova, Stuart L. Schreiber. “A small molecule that binds Hedgehog and blocks signaling in human cells.” Nature Chemical Biology, 5, 154-156, 2009. This article was featured in the Science & Technology Concentrates section of Chemical and Engineering News, 87, 4, 31, 2009. 31. Yingwei Mao, Xuecai Ge, Christopher L. Frank, Jon Madison, Angela N. Koehler, Mary K. Doud, Carlos Tassa, Erin M. Berry, Tracey L. Petryshen, Takahiro Soda, Travis Biechele, Randall T. Moon, Stephen J. Haggarty, Li-Huei Tsai. “DISC1 regulates neural progenitor proliferation via modulation of GSK3b/b-catenin signaling.” Cell, 136, 1017-1031, 2009. Cover image. 32. Shao-En Ong, Monica Schenone, Adam A. Margolin, Xiaoyu Li, Kathy Do, Mary K. Doud, Denkanikota R. Mani, Letian Kuai, Xiang Wang, John L. Wood, Nicola J. Tolliday, Angela N. Koehler, Lisa A. Marcaurelle, Todd R. Golub, Robert J. Gould, Stuart L. Schreiber, Steven A. Carr. “Identifying the proteins to which small- molecule probes and drugs bind in cells.” Proc. Natl. Acad. Sci. USA, 106, 4617-4622, 2009. 33. Angela N. Koehler. “Microarrays in chemical biology.” Chapter, Wiley Encyclopedia of Chemical Biology, Tadhg Begley, Editor, ISBN: 978-0-471-75477-0, 2008. 34. Arturo J. Vegas, Jason H. Fuller, Angela N. Koehler. “Small-molecule microarrays as tools in ligand discovery.” Chem. Soc. Rev., 37, 1385-1394, 2008. 35. Thomas J. F. Nieland, Jared T. Shaw, Firoz A. Jaipuri, Jay. L. Duffner, Angela N. Koehler, Sotirios Banakos, Vassilis I. Zannis, Tom Kirchhausen, Monty Krieger. “Identification of the molecular target for small molecule inhibitors of HDL receptor SR-BI activity.” Biochemistry, 47, 460-472, 2008. 36. Katja Schmitz, Stephen J. Haggarty, Olivia M. McPherson, Jon Clardy, Angela N. Koehler. “Detecting binding interactions using microarrays of natural product extracts.” J. Am. Chem. Soc., 129, 11346-11347, 2007. 37. Arturo J. Vegas, James E. Bradner, Weiping Tang, Olivia M. McPherson, Edward F. Greenberg, Angela N. Koehler, Stuart L. Schreiber. “Fluorous-based small-molecule microarrays for the discovery of histone deacetylase inhibitors.” Angew. Chem. Int. Ed. 46, 7960-7964, 2007. This article was featured in the Science & Technology Concentrates section of Chemical and Engineering News, 85, 40, 30, 2007. 38. Thomas J. F. Nieland, Jared T. Shaw, Firoz A. Jaipuri, Zoltan Maliga, Jay L. Duffner, Angela N. Koehler, Monty Krieger. “Influence of clinical and experimental HDL-cholesterol elevating drugs on the activity of the HDL receptor SR-BI.” J. Lipid Res., 48, 1832-1845, 2007. 39. Hua Miao, John A. Tallarico, Hiroyuki Hayakawa, Karl Münger, Jay L. Duffner, Angela N. Koehler, Stuart L. Schreiber, Timothy A. Lewis. “Ring-opening and ring-closing reactions of a shikimic acid-derived substrate leading to diverse small molecules.” J. Comb. Chem. 9, 245-253, 2007. 40. Jay L. Duffner, Paul A. Clemons, Angela N. Koehler. “A pipeline for ligand discovery using small-molecule microarrays.” Curr. Opin. Chem. Biol. 11, 74-82, 2007. 41. James E. Bradner, Olivia M. McPherson, Angela N. Koehler. “A method for the covalent capture and screening of diverse small molecules in a microarray format.” Nature Protocols, 1, 2344-2352, 2006. 42. Nicola Tolliday, Paul A. Clemons, Paul Ferraiolo, Angela N. Koehler, Timothy A. Lewis, Xiaohua Li, Stuart L. Schreiber, Daniela S. Gerhard, Scott Eliasof. “Small molecules, big players: The National Cancer Institute’s Initiative for Chemical Genetics.” Cancer Res. 66, 1-8, 2006. Cover image. 43. James E. Bradner, Olivia M. McPherson, Ralph Mazitschek, David Barnes-Seeman, John P. Shen, Jasmeet Dhaliwal, Jay L. Duffner, Kristen E. Stevenson, Seung Bum Park, Donna S. Neuberg, Paul Nghiem, Stuart L. Schreiber, Angela N. Koehler. “A robust small-molecule microarray platform for screening cell lysates.” Chem. Biol. 13, 493-504, 2006. This article was featured in the Research Highlights section of Nature Biotechnology, 24, 799, 2006.

Graduate and Undergraduate Studies

44. Angela N. Koehler, Alykhan F. Shamji, Stuart L. Schreiber. “Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis.” J. Am. Chem. Soc. 125, 8420-8421, 2003. 45. David Barnes-Seeman, Seung Bum Park, Angela N. Koehler, Stuart L. Schreiber. “Expanding the functional group compatibility of small-molecule microarrays: discovery of novel calmodulin ligands.” Angew. Chem. Int. Ed. 42, 2376-2379, 2003. Cover image. 46. Paul A. Clemons, Angela N. Koehler, Bridget K. Wagner, Timothy G. Sprigings, David R. Spring, Randall W. King, Stuart L. Schreiber, Michael A. Foley. “A one bead, one stock solution approach to chemical genetics: Part 2.” Chem. Biol. 8, 1183-1195, 2001. 47. Gavin MacBeath, Angela N. Koehler, Stuart L. Schreiber. “Printing small molecules onto microarrays and detecting protein-ligand interactions en masse.” J. Am. Chem. Soc. 121, 7697-7698, 1999. 48. Arthur Glasfeld, Angela N. Koehler, Maria A. Schumacher, Richard G. Brennan. “The role of lysine 55 in determining the specificity of the purine repressor for its operators through minor groove interactions.” J. Mol. Biol. 291, 347-361, 1999.

Patent Applications and License Status

1. “Small Molecule Modulators of the Androgen Receptor.” A. N. Koehler, D. B. Freeman, N. B. Struntz, S. K. Doyle, A. Richters. Massachusetts Institute of Technology. (62/538/471). Exclusively licensed. 2. “Discovery of Small Molecules that Target Androgen Receptor and Uses Thereof.” A. N. Koehler, M. S. Pop. Massachusetts Institute of Technology. (62/538,415). Non-exclusively licensed. 3. Fused 1,3-Azole Derivatives Useful for the Treatment of Proliferative Diseases.” A. N. Koehler, E. Stefan, F. Caballero. Massachusetts Institute of Technology. Exclusively licensed. 4. “MAX Binders as MYC Modulators and Uses Thereof.” A. N. Koehler, E. Stefan, F. Caballero, D. V. Neel, A. Chen. N. B. Struntz, H. L. Evans. Massachusetts Institute of Technology. (62/295,996). Exclusively licensed. 5. “MYC Modulators and Uses Thereof.” A. N. Koehler, F. Caballero, E. Stefan. Massachusetts Institute of Technology. (14/965,549). Exclusively licensed. 6. “Methods for modulating NF-kB.” A. N. Koehler. Harvard University. (61/110,728). 7. “Selective histone deacetylase inhibitors.” A. N. Koehler, J. E. Bradner, J. H. Fuller, N. West. Harvard University. (61/105,589). 8. “Inhibition of Aurora A kinase with spirooxindoles for treatment of cancer, inflammatory, and autoimmune diseases.” K. Münger, A. N. Koehler, H. Hayakawa, C. S. Neumann, M. M. C. Lo, T. A. Lewis, S. L. Schreiber. P.M. Howley. Harvard University. (60/938,362). 9. “Shikimic acid-derived compounds for inhibition and detection of Aurora A-associated tumors.” K. Münger, H. Hayakawa, P. M. Howley, A. N. Koehler, T. A. Lewis, H. Miao, S. L. Schreiber, J. A. Tallarico. Harvard University. (60/841,035) 10. Therapeutic methods using WRN binding molecules.” B. A. Gilchrest, Mark S. Eller, A. N. Koehler, O. M. McPherson, C. S. Neumann, T. A. Lewis. Boston University. (60/823,876). Exclusively licensed. 11. “Small molecule printing.” D. Barnes-Seeman, J. E. Bradner, R. Mazitschek, S. L. Schreiber, A. N. Koehler. Harvard University. (60/755,946). Non-exclusively licensed. 12. "1,3-Dioxane small molecules that bind with high affinity to human papillomavirus type 16 E2 protein." P. Meneses, A. N. Koehler, J. C. Wong, S. L. Schreiber, P. M. Howley. Harvard Medical School. US 2005/0123902. 13. "Printing small molecule microarrays and detecting protein-ligand interactions en masse." S. L. Schreiber, G. MacBeath, A. N. Koehler, P. J. Hergenrother, K. M. Depew. Harvard University. US Patent 6,824,987. Nonexclusively licensed to four companies.

Invited Seminars

1. EPFL, Swiss Institute for Experimental Cancer, Lola & John Grace Distinguished Lecture in Cancer Research, Lausanne, Switzerland. 6/11/20 2. UT Southwestern, Department of Biochemistry, Dallas, TX. 5/21/20 3. Dana-Farber Cancer Immunology and Virology Seminar Series, Boston, MA. 12/9/19 4. Boston University, Freshman Seminar in the Chemical Sciences, Boston, MA. 11/12/19 5. Cancer Research UK-AACR Joint Conference on Engineering and Physical Sciences in Oncology, London, United Kingdom. 10/17/19. 6. Joint Head and Neck Cancer Symposium, Boston University Medical School and Dana-Farber Cancer Institute, Boston, MA. 10/11/19. 7. The Leukemia & Lymphoma Society Translational Research Program Meeting, New York, NY. 9/20/19 8. Cell Press LabLinks: Tools and Tricks for Drugging the Undrugged, Cambridge, MA. 10/3/19. 9. Chemical Biology in the Hub Symposium, Boston, MA. 9/19/19 10. Dana-Farber Chemical Biology Symposium, Boston, MA. 9/6/19 11. Ono Foundation Award Symposium, Boston, MA. 7/1/19 12. Undruggables Summit, Boston, MA. 6/27/19 13. Bayer-Broad Challenging Targets Workshop, Broad Institute, Cambridge, MA. 6/26/19 14. Pfizer, Emerging Science and Innovation Seminar, Cambridge, MA. 6/18/19 15. Gordon Conference Research Seminar: Bioorganic Chemistry (Translational Chemical Biology – Probes and Leads), Proctor Academy, Andover, NH. 6/11/19 16. Gordon Research Conference Seminar: High-Throughput Chemistry & Chemical Biology, New London, NH. 6/2/19 17. Massachusetts General Hospital, Center for Cancer Research Seminar, Charlestown, MA. 5/29/19 18. Drugging Transcription 2019 Conference, Cambridge, MA. 4/25/19 19. University of Wisconsin at Madison, School of Pharmacy Seminar Series, Madison, WI. 4/19/19 20. Harvard University, Harvard Club Faculty Lecture Series, Boston, MA. 4/17/19 21. Therapeutic Innovation Center (THINC) Symposium, Texas Medical Center, Houston, TX. 4/11/19 22. Adenoid Cystic Carcinoma Meeting, Boston, MA. 3/16/19. 23. Tufts University, Pharmacology Seminar, Medford, MA. 3/12/19 24. Women Leaders in Cancer Research Seminar, Broad Institute, Cambridge, MA. 1/18/19 25. Sanofi-Genzyme Oncology Seminar, Cambridge, MA. 12/12/18 26. Boston University, Center for Molecular Discovery, Boston, MA. 12/7/18 27. Boston University, Chemical Biology Seminar Series, Department of Chemistry, Boston, MA. 11/15/18 28. Broad Institute, Staff Scientist Retreat, From Broad to Academia, Wellesley, MA. 5/21/18 29. AACR National Meeting, Session Chair & Speaker, From Chemistry to Clinic: Chemical Probes, Chicago, IL. 4/14/18 30. National Cancer Institute, Frontiers in Targeting Myc: Expression, Regulation and Degradation Meeting, NIH Campus, Bethesda, MD. 4/10/18 31. Rice University, Bioengineering Colloquia Series, Houston, TX. 4/3/18 32. Dana-Farber Cancer Institute, Cancer Leadership Panel, Boston, MA. 3/22/18 33. National Heart, Lung, and Blood Institute Accelerating Cures for Sickle Cell Disease – Small Molecular Therapeutics Workshop, NIH Campus, Bethesda, MD. 3/16/18 34. University of Massachusetts Medical School, Basic Science Keynote Lecture, Medical Scientist Retreat, 3/12/2018. 35. MPM Capital Oncology Impact Fund Summit on Transcription Factors and Cancer, Cambridge, MA. 2/13/18 36. Rutgers New Jersey Medical School, Department of Pharmacology, Newark, NJ. 1/25/18 37. Novartis Pharma AG, Novartis Chemistry Lectureship, Basel, Switzerland. 1/17/18 38. Path to Professorship Series, MIT Media Lab, Cambridge, MA. 11/18/17 39. Broad Institute Chemical Biology & Therapeutic Sciences Series, Cambridge, MA. 10/13/17 40. Third Rock Ventures, Transcription in Oncology, Boston, MA. 08/24/17 41. Gordon Research Conference Seminar: High-Throughput Chemistry & Chemical Biology, Andover, NH. 6/26/17 42. Novartis Institutes for Biomedical Research, Novartis Chemistry Lectureship, Cambridge, MA. 5/23/17 43. Oregon Health Sciences University, Brenden-Colson Center for Pancreatic Care and Department of Physiology and Pharmacology, Portland, OR. 5/11/17 44. Keynote Lecture for Cancer Cell Biology and Molecular Therapeutics Programs Joint Scientific Retreat, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC. 4/6/17 45. AACR National Meeting, Chemical Probes Session, Washington, DC. 4/1/17 46. Deshpande Center IdeaStream Symposium, Cambridge, MA. 3/31/17 47. Boston Children’s Hospital and Dana-Farber Cancer Institute, Pediatric Hematology/Oncology Seminar Series, Boston, MA. 3/16/17 48. Drugging Transcription 2016 Conference, Whitehead Institute, Cambridge, MA. 11/14/16 49. Kendall Square Convergence Symposium, Gene Control for Disease, Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA. 6/1/16 50. Cell Press/Association for Women in Science Symposium – The Science of Gender and the Gender of Science, Cambridge, MA. 5/19/16 51. Deshpande Center IdeaStream Symposium, Cambridge, MA. 4/15/16 52. Dana-Farber Cancer Institute, Center for Functional Cancer Epigenetics, Boston, MA. 2/26/16 53. Broad Institute Epigenomics and Cell Circuits Meeting, Cambridge, MA. 1/11/16 54. Path to Professorship Series, MIT Media Lab, Cambridge, MA. 11/21/15 55. Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA. 10/30/15 56. Broad Institute Cancer Program, Cambridge, MA. 09/01/15 57. Broad Institute Science of Therapeutics Series, Cambridge, MA. 05/28/15 58. Vertex Pharmaceuticals, Boston, MA. 05/28/15 59. New York University, Department of Chemistry, New York City, NY. 05/09/15 60. University of Southern California School of Medicine, Pharmacology Department, Los Angeles, CA. 04/17/15 61. University of Virginia School of Medicine, Cancer Center, Charlottesville, VA. 04/03/15 62. University of Minnesota, Chemical Biology Colloquium Series, Twin Cities, MN. 03/30/15 63. Novartis Institutes for BioMedical Research, Integrated Lead Discovery Group Seminar, Cambridge, MA. 03/27/15 64. Syros Pharmaceuticals, Watertown, MA. 12/10/14 65. Path to Professorship Series, Microsoft NERD Center, Cambridge, MA. 11/15/14 66. Koch Institute, Breaking Cancer: Chemists in the Mix Symposium, Cambridge, MA. 6/26/14 67. Janssen Pharmaceuticals Transcend Scientific Exchange Seminar, Cambridge, MA. 6/11/14 68. Merkin Award Lecture, Broad Institute, Cambridge, MA. 12/11/13 69. Gordon Conference Research Seminar: Bioorganic Chemistry, Proctor Academy, Andover, NH. 6/9/13 70. Yale Chemical Biology Symposium, New Haven, CT. 5/10/13 71. AACR National Meeting, Chair & Speaker, New Paradigms in Molecular Pharmacology Session, Washington, DC. 4/6/13 72. National Cancer Institute, Molecular Discovery Program Seminar Series, Frederick, MD. 4/4/13 73. Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA. 3/21/13 74. Institute for Neurodegenerative Diseases, University of California, San Francisco, CA. 2/28/13 75. RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA. 12/17/12 76. Harvard University, Chemical Biology Practitioner Series, Cambridge, MA. 10/23/12 77. AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations, Boston, MA. 6/30/12 78. Broad Institute Cancer Program Meeting, Cambridge, MA. 6/5/12 79. Cold Spring Harbor Laboratory, Transcription and Cancer Banbury Meeting, Cold Spring Harbor, NY. 4/10/12 80. Baylor College of Medicine, Department of Pharmacology Seminar, Houston, TX. 2/27/12 81. Harvard Medical School Chemical Biology Boot Camp, Cambridge, MA. 1/19/12 82. Harvard University, Chemical Biology Practitioner Series, Cambridge, MA. 10/13/11 83. National Academy of Sciences, Indo-American Kavli Frontiers of Science Symposium, Irvine, CA. 4/21/11 84. GlaxoSmithKline, Adventures in Chemical Biology Seminar Series, Waltham, MA. 12/3/10 85. Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Tumor Biology Visiting Professorship Seminar, Washington, DC. 10/22/10 86. Gordon Research Conference Seminar: High-Throughput Chemistry & Chemical Biology, Les Diablerets, Switzerland. 6/22/10 87. St. Lawrence University, Merck/AAAS Seminar in Chemical Biology, Canton, NY. 04/22/10 88. University of Colorado at Boulder, Organic Chemistry Division Seminar, Boulder, CO. 11/16/09 89. Steacie Institute for Molecular Sciences, Institute Seminar, National Research Council of Canada, Ottawa, ON. 10/15/09 90. Midsummer Nights’ Science at the Broad Institute Series, Cambridge, MA. 7/22/09 91. The Museum of Science, Inspiring Minds: Meet Women in Science Program, Boston, MA. 4/30/09 92. Huntsman Cancer Institute, University of Utah, Stem Cell Symposium on Nuclear Control of Cell Growth and Differentiation, Salt Lake City, UT. 2/23/09 93. Stanford University, Joint Seminar for the Departments of Chemistry and Pathology, Stanford, CA. 2/17/09 94. Princeton University, Department of Chemistry Seminar, Princeton, NJ. 12/2/08 95. MIT, Chemistry-Biology Interface Training Program, Cambridge, MA. 11/24/08 96. Harvard Business School, 9th Annual HBS Health Industry Alumni Seminar. Boston, MA. 11/8/08 97. Schering-Plough, Lead Discovery Group Seminar, Kenilworth, NJ. 4/1/08 98. The Museum of Science, The 13th Annual Symposium on Biotechnology Education, Boston, MA. 3/31/08 99. Massachusetts General Hospital, Center for Cancer Research Seminar, Charlestown, MA. 10/22/07 100. National Research Council of Canada, Genomics and Health Initiative Seminar, Halifax, NS. 5/24/07 101. Harvard University, The 4th Annual National Symposium on the Advancement of Women in Science, Panel Discussion on Drug Discovery, Cambridge, MA. 4/14/07 102. The Salk Institute, Salk/Nature/Ipsen Foundation Symposium on Biological Complexity: Diseases of Transcription, Short Talk, La Jolla, CA. 1/13/07 103. University of Wisconsin at Madison, Genome Center Seminar, Madison, WI. 10/19/06 104. , Life Sciences Institute, Chemical Genomics Colloquium, Ann Arbor, MI. 9/15/06 105. Memorial Sloan-Kettering Cancer Center, Molecular Pharmacology Seminar, New York, NY. 2/20/06 106. University of California, Los Angeles, Department of Chemistry and Biochemistry Seminar, Los Angeles, CA. 1/30/06 107. University of California, Berkeley, Organic Chemistry Seminar, Berkeley, CA. 1/27/06 108. Yale University, Organic Chemistry Seminar, New Haven, CT. 1/9/06 109. Massachusetts General Hospital, Cutaneous Biology Seminar, Charlestown, MA. 3/31/03 110. National Cancer Institute, ICMIC/SAIRP Cancer Imaging Meeting, Herndon, VA. 7/24/02 111. Bauer Center for Genomics, Harvard University, Genomics Research Seminar, Cambridge, MA. 4/17/02

Graduate Students Andrew Chen, MIT Biological Engineering (2013-2019); Shelby K. Doyle, MIT Biological Engineering (2014-); Rohit Thummalapalli, HST MSTP (2014-2016); Robert M. Wilson, MIT Biological Engineering (2015-); Catherine Campbell Henry, MIT Biological Engineering (2017-); Madeleine Sutherland, MIT Chemistry (2017-2019); Julie Urgiles, HST MSTP (2019-)

Visiting Graduate or Medical Students John P. Shen, University of Washington St. Louis (2005-2006); Zahra Bahrami-Nejad, University of Oulu, Finland (2012-2013); Mattheus H. Wildschut, Utrecht University (2015); Rui Traquette, Instituto de Medicina Molecular, Universidade de Lisboa (2017); Jasmin Kruell, Friedrich-Alexander Universität Erlangen (2018); Florian Kabinger, University of Vienna (2019)

Undergraduate Students Nen Cao, Harvard (2004-2006); Jasmeet Dhaliwal, Harvard (2004-2006); Nicole Martinez, University of Puerto Rico (2007-2008); Candice Thompson, Howard University (2010); Ulvi Karaca, METU Ankara (2011); Francisco Alvarez, Harvard (2011-2014); Mayank Choudhary, IIT Madras (2013); Mohammed Toure, Harvard (2013-2016); Elizabeth Trujillo, MIT (2013-2015); Dylan V. Neel, Harvard (2014-2016); Robert M. Wilson, Purdue (2014); Muhammed Ors, Harvard (2016-2017), Katie Ghores, MIT (2015-2017); Hanna Tseng, MIT (2015-); Kristin Frombach, MIT (2015-); Erin McConnell, Reed College (2016); Thomas DePalma, Tufts University (2016); Kimia Ziadkhanpour, MIT (2016-2018); Joseph Espiritu, MIT (2016-2018); Priyanka Jain, Notre Dame (2018); Eesam Hourani, MIT (2018); Ryan Stagg, Boston University (2018-); Brandon Ng, Northeastern University (2020-)

Postdoctoral Fellows Melissa M. Kemp (2011-2014); Francisco Caballero (2013-2014); Cheng Zhong (2013); Jiyoung A. Hong (2014- 2017); Eric Stefan (2014-2016); Qiaoyi Wang (2015); Chuanxu Liu (2015-2016); Helen L. Evans (2015-2018); David B. Freeman (2016-2017); André Richters (2016-); Nicholas B. Struntz (2017-); Brice Curtin (2018-), Yulong Su (2019-), Jasmin Kruell (2019-)

Staff Scientists Olivia M. McPherson (2003-2009); Jay L. Duffner (2004-2006), Anna Borodovsky (2005-2006); Mary Kathryn Doud (2007-2009); Rakhee Busanelli (2009-2013); Clementine Feau (2011-2013); Francisco Caballero (2014- 2016); Marius S. Pop (2014-2016); Becky S. Leifer (2014-); William Walker (2019-)

Funding

1U54 CA231630-01A1 (Linardic, C.) 09/15/19-09/14/24 NIH Identifying and Targeting the Molecular Vulnerabilities of the PAX3-FOXO1 Protein in Rhabdomyosarcoma Fusion-positive alveolar rhabdomyosarcoma (ARMS) remains one of the least understood but most fatal cancers of childhood. A key factor in the disease is a fusion protein called PAX3-FOXO1, which is thought to drive ARMS by dysregulating expression of many genes. But while PAX3-FOXO1 was discovered in 1993, it has not successfully been targeted for treating the disease. Our comprehensive, coordinated approach will identify the genes and proteins required for PAX3-FOXO1’s activity to improve understanding of how the fusion protein is involved in the disease and to identify promising targets for developing new treatments. Our lab will execute large-scale screens to identify new modulators of the fusion, evaluate the phenotypic consequences of perturbation broadly, and synthetically optimize probes that are validated in cellular target engagement studies. Role: PI, Program 3

Emerson Collective Cancer Research Award 08/19/19-08/18/21 Emerson Collective Targeting PAX3-FOXO1 in Fusion-Positive Alveolar Rhabdomyosarcoma This award is focused on the development of targeted-protein degrader compounds capable of post-translational control of PAX3-FOXO1 fusion protein levels in RMS. Role: PI

CAREER Award (Koehler, A.N.) 05/01/19-04/30/2024 National Science Foundation Reprogramming Transcriptional Regulation by Chemical Stabilization of Repressive Homodimers This award enables crystallographic investigation of compounds that stabilize homodimers of transcription factors that repress oncogenic transcription as well as chemical optimization to develop new molecular glues. Role: PI

Frontier Award (Koehler, A.N. and Hammond, P.T.) 06/01/19-05/31/20 Kathy and Curt Marble Cancer Research Fund Lysosome Targeting Chimeras (LYTACS) – Hijacking Lysosomal Pathways for Target-Specific Degradation This collaborative research grant enables the assessment of various lysosomal proteins for their relevance as hijackable targets for the development of chimeric targeting agents to deliver oncogenic proteins for degradation in the lysosome. Specific proof-of-concept experiments involving known peptide and nucleic acid targeting elements will be executed and the discovery of novel small molecule targeting ligands will involve new screens against hijackable proteins. Role: PI

BRIDGE Grant (Koehler, A.N. and Yang, P.) 04/01/19-3/31/20 Dana-Farber Harvard Cancer Center and Koch Institute of MIT Development of Small Molecule Degraders Targeting Hepatitis B Virus This proposal is focused on the development of PROTACs to degrade HBx, a target of interest in HBV viral replication Small molecule microarrays will be used to identify binders to HBx and converted to degraders. Role: PI

ACCRF Grant Award (Koehler, A.N.) 12/01/18-11/30/19 Adenoid Cystic Carcinoma Research Foundation Advancing Chemical Probe Candidates for the MYB Transcription Factor This award is focused on advancing two candidate binders to protein complexes containing MYB and expressed MYB-containing fusions implicated in AML and adenoid cystic carcinoma into mechanism of action studies and chemical optimization. Role: PI

Precision Cancer Medicine Grant 01/01/18-12/31/22 Koch Institute, MIT Center for Precision Cancer Medicine Chemical Probe Discovery for Recalcitrant Targets This ward funds two projects aimed at clarifying the relevance of therapeutic mechanisms involving modulation of protein complexes involving transcription factors and RNA-binding proteins such as Lin28. Role: PI

Pharma Breakthrough Award in Chemical Biology (Koehler, A.N.) 10/01/17-9/30/20 Ono Foundation Small Molecule Approaches to Gene Expression Control This proposal is focused on novel strategies to attenuate oncogenic transcriptional programs by modulating transcriptional complexes via a spectrum of mechanisms using small molecules. Role: PI

Translational Research Program (Koehler, A.N.) 10/01/17-9/30/20 Leukemia and Lymphoma Society Attenuating Myc-Driven Transcription via Modulation of the Max Heterodimer Partner This proposal is focused on pharmacologic evaluation of KI-MS2-008 in a broad spectrum of liquid tumor models, including evaluation of the compound in combination with known pharmacologic agents to understand efficacy, potential for resistance, and other factors. This proposal includes pharmacologic evaluation in leukemias and lymphomas as opposed to broad mechanistic evaluation and new discovery campaigns for Max-protein interactions. Role: PI

Completed Support

Footbridge Grant (Koehler, A.N. and Balk, S.P.) 4/01/18-3/31/19 Dana-Farber Harvard Cancer Center and Koch Institute of MIT Development of Novel androgem Receptor Antagonists for Treatment of Advanced Prostate Cancer This proposal brings together Dr. Steven Balk’s lab with a longstanding focus on targeting AR in advanced PCa, and Dr. Angela Koehler’s lab which has developed novel drug screening approaches and identified a series of candidate small molecules that target a site or sites on the AR NTD and/or DBD. The proposal will focus on advancing the current lead compounds (as well as further screens to identify additional leads), and assessing their activities and mechanisms of action in PCa model systems. If successful, this work will result in the identification of at least one lead compound that is active against the AR in prostate cancers that are resistant to current AR targeted therapies. Subsequent work would then focus on medicinal chemistry to optimize this lead compound for preclinical in vivo studies and phase 1 clinical trials.

Footbridge Grant (Koehler, A.N. and Camargo, F.) 4/01/18-3/31/19 Dana-Farber Harvard Cancer Center and Koch Institute of MIT Targeting the Hippo Pathway in Pancreatic Cancer Invasive pancreatic ductal adenocarcinoma (PDAC) is the most common and deadly cancer of the pancreas. Studies have recently shown that deregulation of YAP, which is normally regulated by the Hippo signaling pathway, drives PDAC progression. YAP is required for the metastasis that leads to invasive PDAC and has become a very exciting target for treating and preventing PDAC and its progression. Given this critical role of the Hippo pathway, we have used advanced chemistry and biology techniques to develop small molecule probes that inhibit YAP’s role in cancerous cells. We will utilize cutting edge medicinal and synthetic chemistry to optimize our drugs as well as exploit various Hippo-YAP pathway specific mouse models to improve treatment and potency. We aim to give rise to a novel, effective and potent therapy against PDAC and metastasis.

AACR-Bayer Innovation and Discovery Award (Koehler, A.N.) 12/01/17-11/30/2018 American Association for Cancer Research Attenuation of Myc-Driven Transcription via a Max-Directed Small Molecule in Lung Adenocarcinoma Inspired by previous work demonstrating eradication of K-ras-driven lung cancer in mice via Omomyc, we now seek to expand in vivo evaluation of KI-MS2-008 to lung adenocarcinoma. We will evaluate biodistribution, toxicity, and efficacy in a conditional mouse model of NSCLC with tumor initiating K-ras activation and loss of p53. We will establish MTD and execute standard PK/PD studies followed by evaluation of efficacy.

Westaway Research Award (Koehler, A.N.) 6/01/17-12/31/18 MIT School of Engineering A Novel Chemical Screening Platform for Androgen Receptor Cistrome Reprogramming In this work, we seek to leverage CRISPR/Cas9 gene editing technology to enable the screening of potential small molecule binders of AR cistrome reprogramming factors for their ability to modulate the AR transcriptional regulatory system as a whole. We will establish a high-throughput platform to catalyze the development of high quality chemical probes for modulating the AR cistrome, ultimately enabling the validation of new therapeutic approaches and catalyzing the development of novel therapeutic agents. Role: PI

Frontier Research Program (Koehler, A.N. and Yaffe, M.B.) 06/01/17-05/31/18 Kathy and Curt Marble Cancer Research Fund Targeting a Resistance Pathway in Castration-Resistant Prostate Cancer – Structural and Biophysical Characterization of Molecules that bind Androgen Receptor Splice Variant This grant focuses on using a broad spectrum of approaches to map the binding mode of unique AR-binding small molecules and to elucidate molecular mechanism of action. Role: Co-PI

Footbridge Grant (Koehler, A.N. and Lane, A.) 4/01/17-3/31/18 Dana-Farber Harvard Cancer Center and Koch Institute of MIT Novel Acute Myeloid Leukemia (AML) Differentiation Therapies Targeting Nucleosome Organization AML is characterized by unchecked proliferation and a block in myeloid differentiation. Yet, nearly all therapies target cell growth without overcoming the differentiation block. We found that HMGN1, a nucleosome binding protein that is recurrently amplified in AML, blocks myeloid differentiation when overexpressed. HMGN1 causes de-compaction of chromatin and alters gene expression. AML blasts have more open chromatin than normal hematopoietic stem cells or more differentiated neutrophils and monocytes. We found that HMGN1 blocks differentiation by opening chromatin and facilitating gene expression at loci that maintain the “stemness” and undifferentiated phenotype of AML. Using small molecules, we intend to target HMGN1 to prevent its normal interaction with chromatin, thus restoring myeloid differentiation in AML. We will apply technologies developed in the Koehler lab to target non-enzymatic proteins and develop this fundamentally novel approach to AML therapy: we will target the structure of chromatin itself, rather than chromatin modifying enzymes or other proliferation pathways.

ACCRF Catalytic Grant (Koehler, A.N.) 9/01/16-1/31/18 Adenoid Cystic Carcinoma Research Foundation Chemical Probe Discovery for MYB This award is focused on preliminary screens to identify candidate binders to MYB and expressed MYB- containing fusions implicated in AML and adenoid cystic carcinoma. Candidates will be evaluated in various transcriptional and other phenotypic assays.

Desphande Center for Technological Innovation (Koehler, A.N.) 09/01/15-08/31/17 Exploring the Therapeutic Potential of Small Molecules that Modulate the c-Myc Oncoprotein An emerging therapeutic strategy involves controlling the function of overactive transcription factors that regulate the expression of established disease genes in cancer. This award will fund further elaboration of the cellular mechanism and molecular of action for two compounds that bind to My and associated proteins that modulate Myc-driven transcription in a cellular setting. We will execute first-pass in vitro and in vivo pharmacologic studies with the goal of establishing preliminary PK/PD data to develop a long-term plan for translational studies.

1R01 CA160860-01A1 (Koehler, AN) 07/01/12-04/30/17 NIH Developing Direct Small-Molecule Probes of Myc-Dependent Transcription The transcription factor c-Myc is involved in regulating expression of 15% of all genes including several that control cell cycle, growth, proliferation, and differentiation. Deregulation of c-Myc occurs through several mechanisms and is one of the most common oncogenic events in human malignancies. c-Myc, like many oncogenic transcription factors, is a promising yet untested target for cancer therapy due to the lack of potent small molecules that directly modulate Myc function in cells. The overall aim of this project is to develop direct small-molecule probes of c-Myc that will be used to study Myc-dependent transcription in normal and neoplastic cells with the goal of clarifying the potential of c-Myc as a therapeutic target.

Starr Cancer Consortium (Luo, M.) 01/01/15-12/31/16 Designing Sinefungin Scaffolds as Specific Protein Methyltransferase Inhibitors Protein methyltransferases (PMTs) regulates numerous epigenetic processes and are frequently hijacked in diseases, in particular cancer, to initialize or maintain the associated pathogenic phenotypes. Few selective small-molecule PMT inhibitors have been documented to date, impairing our ability to advance single-agent or combination cancer therapy through intervening these emerging epigenetic targets. Our recent progress in elucidating sinefungin analogues as selective PMT inhibitors allowed us to formulate the current hypothesis that even closely related PMTs can adopt distinct transient conformations, though not obvious for apo-enzymes, and thus be selectively recognized by small-molecule inhibitors. This proposal aims to expand substantially on the preliminary finding by screening structurally-diverse sinefungin analogues against conformation landscapes of > 60 human PMTs. Our multi-dimensional approach integrates in silico simulation, small-molecule microarrays (SMMs) and in vitro biochemical characterization to establish the streamline of lead identification, scaffold optimization and off-target analysis of PMT inhibitors. This proposal is expected to formulate an unprecedented strategy to rapidly assess PMT inhibitors and present suitable lead compounds for translational studies with cancer therapy as the long-term goal. Role: PI of subaward from MSKCC

Jeptha and Emily V. Wade Award (Koehler, A.N.) 08/01/15-07/31/17 MIT School of Engineering Context-Dependent Modulators of Myc-Driven Transcription in Cancer This award provides seed funding for characterizing the interactome of Myc in various contexts, including in cell lines corresponding to multiple tumors of origin, with the goal of identifying novel Myc-protein interactions that may be suitable targets for probe discovery.

PROTECT (Alter, G.) 10/01/14-12/31/16 DARPA Rapid Immunity via Gene Transfer of Oligoclonal Fc-Enhanced Monoclonal Antibodies This award funds the first phase of a collaboration aimed at using chemical approaches to enhance replicon delivery. Our lab is involved in two projects. The first involves the discovery and development of novel small- molecule adjuvants. The second project involves targeted delivery via nanoparticles equipped with small- molecule targeting elements. Continuation and scale of funding is determined on a quarterly basis. This award is unrelated to the current proposal. Role: PI of subaward from Ragon Institute/MGH

Transcend Award (Koehler, A.N.) 08/01/14-06/30/15 Janssen Pharmaceuticals Targeting Deregulated Transcription Factors in Prostate Cancer This award provides seed funding for developing high-throughput assays focused on identifying modulators of three transcriptional regulators of importance in prostate cancer and expands upon our previous work aimed at identifying modulators of the oncogenic transcription factor ETV1. Assays are focused on identifying modulators of transcription factors in cellularly relevant protein complexes rather than modulators of isolated, intrinsically disordered protein. Role: PI

Merkin Fellowship, Broad Institute (Koehler, A.N.) 12/01/13-12/31/14 Funds are used to support probe discovery for several transcriptional regulators, including transcription factors of relevance to prostate cancer and glioblastoma multiforme (GBM). For example, we are collaborating with the Bernstein lab at MGH, which has identified a set of core transcription factors (TFs) responsible for epigenetic reprogramming of tumor cells into the CSC tumor propagating phenotype. Our project aims to capitalize on these findings by developing small molecule probes which can modulate key “nodes” of this TF network involved in GBM CSC reprogramming and tumor propagation, with the goal of uncovering therapeutic targets.

2R01 HD032067-14A2 (Matzuk, M) 08/17/94-06/30/15 NIH Bone Morphogenic Protein Signaling Pathways in Uterine Biology The Broad’s Molecular Target Discovery and Development Center will oversee the execution of small-molecule microarray screens. The Center will perform steady-state equilibrium and kinetic affinity characterization for lead molecules using surface plasmon resonance. These studies involve building protein surfaces on biosensor chip surfaces and injecting compounds in solution to follow binding interactions in real time. Selected functional lead compounds will serve as starting point for additional chemistry in the Center, including elucidating structure- activity relationships and medicinal chemistry. Role: Collaborator, PI of subaward