Thursday, September 17
11:20 am Conference Registration for Part B Programs
12:20 pm Event Chairperson's Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2020, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction (Sponsorship Opportunity Available)
Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein
William G. Kaelin, Jr., MD, Professor and Investigator, Howard Hughes Medical Institute, Oncology, Dana-Farber Cancer Institute
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.
1:20 KEYNOTE PANEL DISCUSSION:
De-Risking Early Drug Discovery
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
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Andrew Plump, MD, PhD, President, Research & Development, Takeda Pharmaceuticals, Inc.
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing
2:45 Organizer's Welcome Remarks
Cambridge Healthtech Institute
2:50 Chairperson's Remarks
Tomi K. Sawyer, PhD, President & Chief Drug Hunter, Maestro Therapeutics
2:55 High-Throughput Virtual Screening for Discovery of Novel and Selective Allosteric Inhibitors of Human EAAT2
MarieLaure Rives, PhD, Principal Scientist, Cellular & Molecular Pharmacology, Janssen Pharmaceuticals Inc.
Major neuropsychiatric and neurological disorders are characterized by dysregulation of glutamatergic neurotransmission. Slowing glutamate uptake with selective sodium-dependent glutamate transporters (EAAT1–5) inhibitors could improve transmission at glutamatergic synapses and provide therapeutic benefit under some conditions. Understanding the precise role of EAAT2 in health and disease requires identification of new selective EAAT2 modulators. In this study, we applied structure-based tools to the discovery of a novel and selective allosteric hEAAT2 inhibitor.
3:25 Robust Hit Triage Funnels for Biochemical High-Throughput Screening
Nava Krishnan, PhD, Senior Scientist, Molecular Screening & Characterization, AbbVie Inc.
High-throughput screening (HTS) is a powerful strategy in drug discovery to identify chemical starting points for drug discovery and tool compounds for chemical biology, respectively. Although small molecule drug discovery efforts have largely focused on enzymes and GPCRs, there has been an increased desire for identifying small molecules as modulators of protein complexes. Such difficult targets require more sophisticated HTS-compatible binding and activity assays. However, these newer HTS approaches are hampered by generating a large percentage of undesirable hits. Thus, appropriate triaging strategies are required to identify quality hits, and here we discuss such strategies.
The talk will summarize our most recent development efforts to facilitate drug discovery activities targeting KRAS signaling pathway. We have produced the full spectrum of pathway proteins, including wild-type and mutated KRAS, several GEFs, GAP, and kinases. We have established and validated a number of biochemical and biophysical assays for these targets, including the direct inhibition of mutated KRAS activities and RAS-SOS1 interactions.
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
Towards Macrocyclic Peptide Therapeutics Using mRNA-Encoded Libraries
Wayne J. Fairbrother, DPhil, Director & Senior Staff Scientist, Early Discovery Biochemistry, Genentech Inc.
Development of small molecules modulating protein-protein interactions can be difficult due to large and shallow interaction interfaces. Antibodies are ideal for targeting PPIs, but they lack cell permeability. Macrocycles occupy an intermediate space between small molecules and antibodies, having sufficient size and functionality to interact specifically and with high affinity with PPI surfaces. Accordingly, mRNA display is a highly valuable technology to identify and optimize peptide-based macrocycles.
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.
6:00 From DNA-Encoded Library Hits to Drug Leads: A Case Study
Christopher B. Phelps, PhD, Director, Medicine Design, GlaxoSmithKline
6:30 Dinner Short Course Registration (Premium Package or separate registration required)
7:00 Dinner Short Courses 10-12 (see Short Courses page for details)
9:30 Close of Day
Friday, September 18
7:00 am Registration
7:30 Interactive Breakfast Breakout Discussion Groups
Grab a cup of coffee 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. Visit the conference website for discussion topics and moderators.
8:30 Transition to Sessions
8:40 Chairperson's Remarks
Samantha J. Allen, PhD, Principal Scientist, Lead Discovery & Profiling, Janssen R&D LLC
8:45 Talk Title to be Announced
Beth A. Knapp-Reed, PhD, Scientific Leader, Medicinal Chemistry, Platform Technology & Science, GlaxoSmithKline
9:15 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.
9:45 From Fragment to Clinical Candidate: The Role of Biophysical Methods in Protein-Protein Interaction (PPI) Inhibitor Development
Chiara R. Valenzano, PhD, Senior Research Associate, Molecular Science, Astex Pharmaceuticals
This talk will offer the opportunity to discuss the impact that biophysical methods can have at different stages of the drug discovery process. By presenting case studies taken from the Astex pipeline, the advantages and limitations of applying biophysical techniques, such as NMR, SPR, and X-ray crystallography, to fragment-based drug discovery will be discussed.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
Taking a Tailored Approach to Fragment Screening
Claudia De Fusco, PhD, Senior Scientist, AstraZeneca
A presentation describing the application of flexible approaches to fragment-based lead generation, whereby choice of screening method and fragment sets to test are tailored to the bespoke project needs and target feasibility. Several examples of AstraZeneca projects will be used to illustrate a number of screening strategies and subsequent chemical optimisation from hits to leads.
11:25 Optimizing a Fragment Hit into Undruggable Space: A Case Study
Justin Dietrich, PhD, Senior Scientist III, Fragment Based Drug Discovery, AbbVie
We present a story about growing a small molecule fragment to an oral drug candidate with in vivo efficacy for a PPI program. We optimized a fragment into undruggable space to learn about the protein target and then used that information and tools generated along the way to guide a second fragment program that focused on efficiency and maintaining drug-like properties for the final drug candidate.
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 collabor vault.
12:10 Sponsored Presentation (Opportunity Available)
12:25 Session Break
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Refreshment Break in the Exhibit Hall with Poster Viewing
1:50 Chairperson's Remarks
Joe Patel, PhD, Director, Structural Biology, C4 Therapeutics Inc.
Degrader-Induced Ternary Complex Modeling
Scott Eron, PhD, Research Scientist II, C4 Therapeutics, Inc.
2:25 Characterization of Novel STING Ligands Using SPR and Orthogonal Approaches
Gottfried Schroeder, PhD, Senior Scientist, Quantitative Biosciences, Merck & Co., Inc.
Modulation of the innate immune receptor, STING, is of pharmacological interest for both oncology and autoimmune indications. Binding of cyclic dinucleotide 2’3’-cGAMP to dimeric STING stabilizes a ‘lid-closed’ protein conformation, ultimately inducing interferon production. Biophysical characterization of different classes of STING ligands using surface plasmon resonance (SPR) has revealed significant differences in binding kinetics, stoichiometry and mode of action. The results of complimentary techniques further support these observed mechanistic differences.
2:55 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.
3:25 Presentation to be Announced
3:55 Close of Conference