Cambridge Healthtech Institute’s 4th Annual

Lead Generation Strategies

Small Molecule Hits to Quality Drug Leads via Biophysical and Other New Approaches

September 17 - 18, 2020 ALL TIMES EDT

This conference focuses on how discovery chemists choose which compounds to optimize into drug leads from the many small-molecule compounds that arise from combining newer hit-finding strategies, such as encoded libraries, fragment-based drug design (FBDD), and biophysical screening approaches with classical high-throughput screens. Drug discovery colleagues from pharma, biotech, and academia convene to share new biophysical techniques and discuss applying orthogonal approaches for more efficient and successful ‘hit to lead’ drug development endeavors.

Thursday, September 17

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PANEL AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
  • Data Sciences
  • ​Novel Chemical Modalities
  • Investment and Partnering Models
  • COVID-19 Progress as Examples of Successful Partnerships
Panelists:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Stephen A. Hitchcock, PhD, Head, Research, Takeda Pharmaceuticals, Inc.
1:35 pm Lunch Break - View Our Virtual Exhibit Hall

EXPANDING CHEMICAL SPACE

2:05 pm

A Solution Phase Platform to Characterize Chemical Reaction Compatibility with DNA-Encoded Chemical Library Synthesis

Anokha S. Ratnayake, PhD, Principal Scientist, Design and Synthesis Sciences, DNA Encoded Library Technology Group, Pfizer Global R&D Groton Labs

The growing scope of chemistries for DNA-encoded chemical library (DECL) synthesis has intensified the need for quantitative methods for validating their compatibility with DNA. We have developed a comprehensive approach for the assessment of chemical fidelity (reaction yield and purity), encoding fidelity (ligation efficiency), and readability (DNA compatibility), revealing the fate of the DNA-tag during DECL chemistry from a single platform. I will describe its utility in screening on-DNA chemistries.

2:25 pm

Development of Scaffold-Diverse, Stereochemically Rich DNA-Encoded Libraries and Their Application to Targeting the “Undruggable” Proteome

Thomas Kodadek, PhD, Professor of Chemistry, The Scripps Research Institute; Co-Founder, Deluge Biotechnologies

DNA-encoded libraries (DELs) are increasingly popular as a source of protein ligands. An important issue moving forward is to develop more structurally diverse and stereochemically complex DELs, particularly with respect to “largish” molecules, such as non-peptidic macrocycles that may be suitable for targeting difficult-to-drug proteins, such as transcription factors. Recent efforts along these lines will be described.

2:45 pm From DNA-Encoded Library Hits to Drug Leads: A Case Study
Christopher B. Phelps, PhD, Director, Medicine Design, GlaxoSmithKline

Inhibitors of Myc identified from DNA-encoded library screens of p300. Hits from a 2009 DEL affinity screen of p300 were incorporated into GSK’s HTS screening deck as part of routine compound collection enhancement. These compounds were identified in a phenotypic HTS for Myc inhibition which allowed for rapid target deconvolution and follow on DEL screens for additional chemical series.

Ekaterina Kuznetsova, PhD, Director, Product Development, Reaction Biology

This talk will introduce Reaction Biology’s KRAS Pathway Drug Discovery suite including the full spectrum of recombinant KRAS pathway proteins such as wild type and mutated KRAS, GEFs, GAP, and kinases as well as established biochemical and biophysical assays including the direct inhibition of mutated KRAS activities and RAS-SOS1 interactions. 

3:25 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Tomi K. Sawyer, PhD, Chief Drug Hunter & President, Maestro Therapeutics
Panelists:
Anokha S. Ratnayake, PhD, Principal Scientist, Design and Synthesis Sciences, DNA Encoded Library Technology Group, Pfizer Global R&D Groton Labs
Thomas Kodadek, PhD, Professor of Chemistry, The Scripps Research Institute; Co-Founder, Deluge Biotechnologies
Christopher B. Phelps, PhD, Director, Medicine Design, GlaxoSmithKline
Ekaterina Kuznetsova, PhD, Director, Product Development, Reaction Biology
3:45 pm Happy Hour - View Our Virtual Exhibit Hall
4:15 pm Close of Day

Friday, September 18

FRAGMENT AND STRUCTURE-BASED DRUG DISCOVERY

10:00 am Fast NMR Structure Determination of Protein-Fragment Complexes
Julien Orts, PhD, Assistant Professor, Physical Chemistry Lab, ETH Zurich

Although the evolution from initial fragment to advanced hit or lead is possible without routine crystallographic support, high-resolution structures of the protein–fragment complex greatly facilitate the process. However, it can be challenging to routinely obtain these crystals. In these instances, NMR spectroscopy is the method of choice to guide the medicinal chemistry campaign. I present case studies of recent NMR structure-based drug design for fragments.

10:20 am

Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design

Justin Dietrich, PhD, Principal Research Scientist I, Fragment Based Drug Discovery and DNA-Encoded Library Technologies, AbbVie

Inhibition of TNFα and other cytokine signaling pathways such as IL-17, IL-23, and IL-6 have been clinically validated via macromolecular biologic drugs; however, efforts to modulate these pathways with small molecules by directly inhibiting interaction with their cognate receptors have been impeded by the challenges associated with the requirements of a small molecule to disrupt high-affinity, protein-protein interactions.  Here, we will present a fragment-based approach that was leveraged to develop orally efficacious TNFα inhibitors that function through an allosteric desymmetrization mechanism.

10:40 am

Finding a Way Out of the Labyrinth: Degrader-Induced Ternary Complex Modelling

Scott Eron, PhD, Research Scientist II, C4 Therapeutics, Inc.

With the exponential growth in the development of targeted protein degraders comes significant challenges for the structural biology and computational modelling communities. Numerous examples now exist in the literature of the exquisite SAR possible through modifications of these molecules and this has driven a need to generate atomic level ternary complex information to assist degrader design and elucidate mechanism of action. Here we will present our approach combining biophysical and computational methods to generate weighted models to support medicinal chemistry campaigns.

Whitney Smith, PhD, Director of New Business Development, Sales, Collaborative Drug Discovery

Research of tomorrow is moving towards a more collaborative, open source and platform-independent environment. CDD Vault facilitates more effective research and collaboration by easing the chemical and biological complexity of drug discovery with chemical and batch registration, data visualization and an ELN integrated into a private, secure and collaboration vault. 

11:20 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Joe Patel, PhD, Senior Director, Biochemistry Biophysics & Crystallography, C4 Therapeutics, Inc.
Panelists:
Julien Orts, PhD, Assistant Professor, Physical Chemistry Lab, ETH Zurich
Justin Dietrich, PhD, Principal Research Scientist I, Fragment Based Drug Discovery and DNA-Encoded Library Technologies, AbbVie
Scott Eron, PhD, Research Scientist II, C4 Therapeutics, Inc.
Whitney Smith, PhD, Director of New Business Development, Sales, Collaborative Drug Discovery
11:40 am Coffee Break - View Our Virtual Exhibit Hall

APPLYING BIOPHYSICAL TOOLS

11:55 am

Adapting Label-Free Biosensing to Increasingly Diverse Chemical Matter

 

John Quinn, PhD, Principal Scientist, Biophysical Group, Biochemical and Cellular Pharmacology, Genentech

Increasingly diverse chemical matter arising from new therapeutic modalities require biophysical data to inform the often-complex structure-function relationship but such data is more challenging to acquire. Real-time label-free biosensing assays can help meet the growing need for identification and mechanistic characterization of diverse chemical matter. A variety of novel assays are presented with reference to example data from early discovery projects at Genentech.

12:15 pm Biophysical Techniques to Identify Aggregating Compounds and Select Hits
Samantha J. Allen, PhD, Principal Scientist, Lead Discovery & Profiling, Janssen R&D LLC

Small-molecule drug discovery can be hindered by aggregating compounds that act as non-selective inhibitors of drug targets. These aggregates appear as false positives in high-throughput screening campaigns and can complicate structure-activity relationships during triage and compound optimization. They can also cause problems in secondary biophysics assays, such as SPR. I’ll discuss high-throughput microplate-based approaches to identify compound aggregation.

Stina Lundgren, Principal Project Advisor, Pelago Bioscience

Confirmation of target engagement in relevant physiological environment ensures successful drug discovery and the right project prioritization. Welcome to learn about the CETSA methodology and principles for compound profiling including tool finding, primary screening, hit confirmation and generation of relevant structure-activity relationship (SAR) data.

12:55 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Gottfried Schroeder, PhD, Senior Scientist, Quantitative Biosciences, Merck & Co., Inc.
Panelists:
John Quinn, PhD, Principal Scientist, Biophysical Group, Biochemical and Cellular Pharmacology, Genentech
Samantha J. Allen, PhD, Principal Scientist, Lead Discovery & Profiling, Janssen R&D LLC
Stina Lundgren, Principal Project Advisor, Pelago Bioscience
1:15 pm Refresh Break - View Our Virtual Exhibit Hall
1:25 pm Brown Bag Lunch and Interactive Breakout Discussions - View Our Virtual Exhibit Hall

Grab your own lunch and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Discussion topics and moderators will be listed on the website.


BREAKOUT: Role of Structural Biology and Molecular Modeling during Drug Lead Generation

Maricel Torrent, PhD, Principal Research Scientist, Molecular Modeling, AbbVie Inc.

 

  • What key questions can be answered by early protein models and structures to help triage and advance hits?
  • Crystal structures vs. 3D protein homology models?  Multiple domains, protein partners?  Medchem strategy selection?
  • Early assessment of binding site(s) and projected growth/potential of each chemotype/series?
2:00 pm

SAR by 19F NMR: Using Protein-Observed Fluorine NMR for Targeting Protein Complexes

William CK Pomerantz, PhD, Associate Professor, Medicinal Chemistry, University of Minnesota Twin Cities
Inhibitor discovery for protein-protein interactions has proven difficult due to the large protein surface areas and dynamic interfaces. To address this challenge, structural biology approaches for fragment-based ligand discovery have had a significant impact on advancing small molecule inhibitors into the clinic. Inspired by the protein-observed NMR approach using 1H-15N-HSQC NMR, we have applied a complementary protein-observed 19F NMR (PrOF NMR) approach using 19F-labeled side-chains that are enriched at protein-protein-interaction interfaces. This talk will describe several case studies where PrOF NMR has been applied for fragment screening, ligand deconstruction, and screening of protein mixtures. Several new inhibitors of epigenetic complexes will  be highlighted. 



2:20 pm

Biophysical Studies of Human GPCR Allosteric Modulators

Matthew T. Eddy, PhD, Assistant Professor, Chemistry, University of Florida, Gainesville

We leverage nuclear magnetic resonance in solution to provide fresh insights into the structural mechanisms of partial agonism in human GPCRs. We also describe NMR studies of endogenous GPCR allosteric modulators (e.g. lipids) and their impact on function-related dynamics.

2:40 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Ben J Davis, PhD, Research Fellow, Biology, Vernalis R&D Ltd
Panelists:
William CK Pomerantz, PhD, Associate Professor, Medicinal Chemistry, University of Minnesota Twin Cities
Matthew T. Eddy, PhD, Assistant Professor, Chemistry, University of Florida, Gainesville
3:00 pm Close of Conference





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