Emerging Paradigms in Drug Discovery & Chemical Biology

Emerging Paradigms in Drug Discovery & Chemical Biology

Tuesday, October 25, 2016

The New York Academy of Sciences

Chemical Biology is changing the face of drug discovery. Over the past decade, chemistry based approaches have facilitated unprecedented advances in our understanding of cell biology and animal physiology, and have proven highly useful for drug discovery, demonstrating success not only in target and mechanism identification, but also in target validation and off-target identification. This symposium will highlight recent advances in on-target and off-target identification of drug-protein interactions in physiologically relevant systems, and will feature talks on the ubiquitin proteasome system, GPCRs, protein lipidation mechanisms, neurobiology, and cancer.

Registration Pricing

Member$60
Member (Student / Postdoc / Resident / Fellow)$25
Nonmember (Academia)$105
Nonmember (Corporate)$160
Nonmember (Non-profit)$105
Nonmember (Student / Postdoc / Resident / Fellow)$70

This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City where possible.

Webinar Pricing

Member$30
Member (Student / Postdoc / Resident / Fellow)$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

Agenda

* Presentation times are subject to change.


Tuesday, October 25th, 2016

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, New York Academy of Sciences
Erik Hett, PhD, Biogen

9:15 AM

Chemical Reporters for Exploring Host–Microbe Interactions
Howard Hang, PhD, The Rockefeller University

9:55 AM

Chemical–Proteomic Strategies to Investigate Reactive Cysteines
Eranthie Weerapana, PhD, Boston College

10:35 AM

Networking Coffee Break

10:55 AM

Comprehensive Drug Target Profiling Using Complementary Chemoproteomics Technologies
Marcus Bantscheff, PhD, Cellzome / GSK
* This speaker will not be sharing his slides as part of the webcast.

11:35 AM

Small Molecule Inducers of Pyroptosis
Daniel Bachovchin, PhD, Memorial Sloan Kettering Cancer Center

12:15 PM

Networking Lunch and Poster Session

1:45 PM

Identification and Validation of Drug–Protein Interactions in Physiologically Relevant Systems
Brian Raymer, PhD, Pfizer

2:25 PM

Oncogenic K-Ras Signaling and Drug Discovery
Ruth Nussinov, PhD, National Cancer Institute
* This speaker will not be sharing her slides as part of the webcast.

3:05 PM

Networking Coffee Break

3:35 PM

Illuminating the Hidden GPCR-ome
Bryan Roth, PhD, University of North Carolina
* This speaker will not be sharing his slides as part of the webcast.

4:15 PM

PROTACS: Inducing Protein Degradation as a Therapeutic Strategy
Craig Crews, PhD, Yale University

4:55 PM

F1000Research Poster Award Presentation and Closing Remarks
Doug Johnson, PhD, Pfizer

5:00 PM

Networking Reception

6:00 PM

Adjourn

Organizers

Mercedes Beyna, MS

Biogen

Dario Doller, PhD

Concert Pharmaceuticals

Sonya Dougal, PhD

The New York Academy of Sciences

Erik Hett, PhD

Biogen

Doug Johnson, PhD

Pfizer

Caitlin McOmish, PhD

The New York Academy of Sciences

Brian Raymer, PhD

Pfizer

Roland Staal, PhD

New Jersey Economic Development Authority

Speakers

Daniel Bachovchin, PhD

Memorial Sloan Kettering Cancer Center

Marcus Bantscheff, PhD

Cellzome/GSK

Dr. Marcus Bantscheff serves as Head of Technology, at Cellzome, a GSK company. Marcus received his PhD in biochemistry at the University of Rostock. In 2002 he joined Cellzome AG, at that time a privately owned drug discovery company, that was subsequently acquired by GlaxoSmithKline in 2012. Marcus' research focuses on the development and application of proteomics and chemical biology approaches to characterize targets and mechanism-of-action of bioactive molecules. In his current position, he leads the proteomics platform at Cellzome/GSK. Marcus has co-authored more than 50 publications and is a member of the Scientific Advisory Board of Denator AB.

Craig Crews, PhD

Yale University

Dr. Crews is the Lewis B. Cullman Professor of Molecular, Cellular and Developmental Biology and holds joint appointments in the departments of Chemistry and Pharmacology at Yale University. He graduated from the U.Virginia with a BA in Chemistry and received his PhD from Harvard University in Biochemistry. Dr. Crews has a foothold in both the academic and biotech arenas; on the faculty at Yale since 1995, his laboratory has pioneered the use of small molecules to control intracellular protein levels. In 2003, he co-founded Proteolix, Inc., whose proteasome inhibitor, Kyprolis™ received FDA approval for the treatment of multiple myeloma. Since Proteolix's purchase by Onyx Pharmaceuticals in 2009, Dr. Crews has focused on a new 'induced protein degradation' drug development technology, PROTACs, which served as the founding IP for his latest New Haven-based biotech venture, Arvinas, Inc. Currently, Dr. Crews serves on several editorial boards and is Editor of Cell Chemical Biology. In addition, he has received numerous awards and honors, including the 2013 CURE Entrepreneur of the Year Award, 2014 Ehrlich Award for Medicinal Chemistry, 2015 Yale Cancer Center Translational Research Prize and a NIH R35 Outstanding Investigator Award (2015).

Howard Hang, PhD

The Rockefeller University

Howard C. Hang is an Associate Professor and Head of the Laboratory of Chemical Biology and Microbial Pathogenesis at The Rockefeller University. He obtained his BS degree in chemistry from the University of California, Santa Cruz, 1998 with Professor Joseph P. Konopelski. In 2003, he completed his PhD in chemistry at University of California, Berkeley, with Professor Carolyn Bertozzi. During his graduate studies, he was awarded an American Chemical Society, Organic Division, Graduate Fellowship. He then worked with Professor Hidde Ploegh at Harvard Medical School and the Whitehead Institute of Biomedical Research at Massachusetts Institute of Technology from 2004 through 2006 as Damon Runyon Cancer Research Foundation Postdoctoral Fellow. He joined the faculty at The Rockefeller University in 2007. He received Irma T. Hirschl Early Career Scientist Award in 2007, Ellison Foundation New Scholar in Aging Award in 2008, Distinguished Teaching Award from The Rockefeller University in 2011 and Eli Lilly Award in Biological Chemistry from American Chemical Society Division of Biological Chemistry in 2017. The Hang laboratory is interested in developing chemical tools for elucidating fundamental mechanisms of host–microbe interactions and developing new therapeutic strategies to combat microbial infections.

Ruth Nussinov, PhD

National Cancer Institute
website

Ruth Nussinov graduated from Rutgers, was in the Weizmann Institute, the Chemistry Department at Berkeley and Biochemistry at Harvard. She joined the Medical School in Tel Aviv and accepted a concurrent position at the National Cancer Institute, Leidos. She has co-authored over 550 papers. She is the Editor-in-Chief in PLoS Computational Biology, and an Associate Editor and on the Editorial Boards of several journals. She is a frequent speaker in Domestic and International meetings, symposia and academic institutions, won several awards and elected fellow of several societies. Her National Cancer Institute website describes her science, and major contributions.

Brian Raymer, PhD

Pfizer

Brian Raymer received his BA in Chemistry from Saint Olaf College. Following work at Pfizer in process research and development, he obtained his PhD in Chemistry and Chemical Biology from Harvard University working with Professor David Evans on the total synthesis of azaspiracid. Subsequently, he joined Novartis working on medicinal chemistry programs in the diabetes and cardiovascular disease areas in addition to chemical biology and bioconjugation efforts. He then moved to Pfizer where he is currently Senior Principal Scientist involved in medicinal chemistry and chemical biology projects in the cardiovascular and metabolic disease areas.

Bryan Roth, MD, PhD

University of North Carolina

Bryan Roth MD, PhD is the Michael Hooker Distinguished Professor of Pharmacology at UNC Chapel Hill Medical School. Dr. Roth's lab studies the structure and function of G-protein coupled receptors (GPCRs) and develops novel chemical biology and systems pharmacology approaches for drug discovery and chemogenetics. Dr. Roth is a member of the National Academy of Medicine of the National Academy of Sciences, has given many named lectures and won many awards for his research. Dr. Roth published more than 400 papers and given more than 300 invited talks. Dr. Roth is a frequent consultant to pharmaceutical and biotechnology companies in the areas of drug discovery and safety pharmacology.

Eranthie Weerapana, PhD

Boston College

Eranthie Weerapana received her BS in Chemistry from Yale University. She received her PhD in Chemistry from MIT, where she worked with Professor Barbara Imperiali, investigating glycosyltransferases involved in N-linked glycosylation in the gram negative bacterium Campylobacter jejuni. She then performed postdoctoral studies at The Scripps Research Institute, La Jolla where she worked with Professor Benjamin F. Cravatt to develop chemical-proteomic methods to investigate reactive cysteines in complex proteomes. Eranthie started her independent research career in 2010 at Boston College, where she is currently an Assistant Professor of Chemistry. Her interdisciplinary research program focuses on applying mass-spectrometry methods to identify regulatory cysteine residues in the human proteome, and chemical biology approaches to develop covalent small-molecule modulators for these cysteine-mediated protein activities. Her research group combines tools from organic synthesis, cell and molecular biology and mass spectrometry-based proteomics.

Eranthie's awards include a Smith Family Award for Excellence in Biomedical Sciences (2011) and a Damon Runyon-Rachleff Innovation Award (2012).

Sponsors

This program is supported in part by educational grants from AbbVie, Bristol-Myers Squibb, and Merck and Co., Inc.

Academy Friends

Janssen Research and Development, Johnson & Johnson

MilliporeSigma

Promotional Partners

The American Physiological Society

American Society for Pharmacology & Experimental Therapeutics (ASPET)

Current Opinion in Chemical Biology

The Dana Foundation

Drug Discovery Today

GRO-Biotech

Nature

NewYorkBio

Society for Laboratory Automation and Screening

Tri-Institutional PhD Program


The Biochemical Pharmacology Discussion Group and the Chemical Biology Discussion Group are proudly supported by

  • Boehringer Ingelheim
  • Regeneron

Premiere Supporter

  • Pfizer

Abstracts

Chemical Reporters for Exploring Host–Microbe Interactions
Howard Hang, PhD, The Rockefeller University

Posttranslational modifications (PTMs) of proteins with key metabolites (phosphate, acetate, glycans, lipids) provide critical mechanisms to control cellular pathways in biology. These metabolites can be acquired from the extracellular milieu or synthesized in cells, and provide direct biochemical mechanism(s) to regulate the activity of proteins in cells. The biochemical analysis of purified proteins and large-scale proteomic studies have revealed an incredible diversity and abundance of PTMs on proteins. Nonetheless, quantifying dynamic and regulated PTMs on proteins and determining their precise function in specific cellular pathways is still a major challenge in biology and human disease. To address these challenges, my laboratory has developed specific metabolite chemical reporters bearing uniquely reactive groups that can be enzymatically incorporated onto proteins in vitro and in vivo and selectively labeled with bioorthogonal reagents for imaging or proteomics studies. The chemical reporters we have developed provide robust tools to visualize and profile diverse protein modifications (fatty-acylation, prenylation, acetylation, AMPylation and ADP-ribosylation, in bacteria, yeast and mammalian cells. Notably, these chemical reporters have allowed my laboratory to demonstrate regulated and quantitative changes in protein fatty-acylation can control the function of specific proteins and cellular phenotypes. In addition, my laboratory has used these chemical reporters to discover new roles for protein lipidation in eukaryotic cellular differentiation, innate immunity as well as pathogen virulence. These chemical tools from my laboratory are thus providing new opportunities to characterize protein modifications by metabolites in host-microbe interactions and other areas of biology.

Comprehensive Drug Target Profiling Using Complementary Chemoproteomics Technologies
Marcus Bantscheff, PhD, Cellzome/GSK

The discovery of innovative, safe and efficacious drugs is hampered by a multitude of challenges. For example off-target effects or inefficient target engagement are frequent causes for late stage failure of candidate drug molecules. The discovery of innovative therapeutic approaches, however, critically depends on our ability to identify the mechanisms of action of bioactive molecules. In order to address some of these fundamental challenges in drug discovery, we have developed several (chemo-)proteomics approaches that allow the comprehensive analysis of cellular targets of bioactive compounds in live cells and correlation of target engagement with effects on the proteotype. This presentation describes experimental strategies in current chemical proteomics research, discusses recent examples of successful applications, and highlights areas in drug discovery where proteomics has impact.

Small Molecule Inducers of Pyroptosis
Daniel A. Bachovchin, PhD, Assistant Member, Chemical Biology Program, Memorial Sloan Kettering Cancer Center

Val-boroPro (talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of mechanistic understanding, Val-boroPro has attracted significant interest as a potential anticancer agent, reaching Phase III trials in humans. Here I will discuss our recent finding that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. We have demonstrated that the inhibition of two serine proteases, DPP8 and DPP9, activates the proprotein form of caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1β, but does cleave and activate gasdermin D to induce pyroptosis. Mice lacking caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identifies the first small molecule that induces pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.

Identification and Validation of Drug–Protein Interactions in Physiologically Relevant Systems
Brian K. Raymer, PhD, Pfizer, Cambridge, MA

Chemical probes are important tools used to characterize human biology at a molecular level. Because therapeutic targets based on compelling human biology are more likely to yield new medicines, working in physiologically relevant systems is imperative when attempting to identify and validate targets. This presentation highlights two target characterization efforts using chemical probes in physiologically relevant systems. Specifically, the presentation illustrates the use of a chemogenomics compound library to identify a novel mechanism modulating apoE levels in an astrocyte model of Alzheimer's disease and a sulfonyl fluoride chemical probe to validate target engagement in a peripheral blood mononuclear cell model of spinal muscular atrophy.

Chemical–Proteomic Strategies to Investigate Reactive Cysteines
Eranthie Weerapana, PhD, Boston College

Cysteine residues play diverse functional roles in proteins, including catalysis, metal-binding, structural stabilization and redox regulation. These functional cysteines are highly reactive and can be targeted by irreversible inhibitors. We aim to identify new functional cysteines within the human proteome and develop chemical probes to covalently modify these residues. To achieve this, we have developed a chemical-proteomic platform to identify cysteines that are highly sensitive to S-nitrosation, which is a posttranslational modification known to regulate protein activity and localization. We identified several previously unannotated cysteines and demonstrate that they allosterically regulate protein activity through S-nitrosation. In order to develop chemical probes to modify these and other functional cysteines in the proteome, a library of cysteine-reactive small-molecules was generated. Our initial library is based on a trifunctionalized 1,3,5-triazine scaffold, from which a potent and selective cysteine-reactive inhibitor for protein disulfide isomerase was identified. Our studies illustrate the potential of irreversible cysteine-targeted inhibitors as pharmacological agents for a large subsection of the proteome.

PROTACS: Inducing Protein Degradation as a Therapeutic Strategy
Craig M. Crews, PhD, Yale University

The current 'inhibitor/binder-based' paradigm of pharmaceutical control has inherent limitations: 1) the need to achieve/maintain high systemic exposure to insure sufficient in vivo protein inhibition, 2) potential off-target side effects due to high in vivo concentrations, and 3) the need to bind to an active site, thus limiting the potential 'drug target space' to a fraction of the proteome. Alternatively, induced protein degradation lacks these limitations. Based on an 'Event-driven' paradigm, this approach offers a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins. This is achieved via recruitment of target proteins to the cellular quality control machinery, i.e., the Ubiquitin/Proteasome System (UPS) using PROTACs (Proteolysis Targeting Chimeras) that can achieve 'degradation concentrations' (DC50 values) in the picomolar range. This knockdown technology has been shown to effectively decrease intracellular levels of a variety of target protein classes, including kinases, transcription factors and epigenetic readers.

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