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
Ajay S. Yekkirala, PhD, Co-Founder & CSO, Blue Therapeutics
2:55 KEYNOTE PRESENTATION:
The Essential Role of Pharmacological Assays and Models in the Lead Optimization Stage of Drug Discovery
Terrence P. Kenakin, PhD, Professor, Pharmacology, University of North Carolina at Chapel Hill
Drugs interact with ongoing living physiology to produce therapeutic effect and drugs may induce varying behaviors in different tissues in vivo. Estimates of drug activity are obtained in test systems (rarely directly in the therapeutic system) and such ‘snapshots’ of activity need to be expanded into the complete ‘movie’ of in vivo effects to accurately gauge therapeutic utility. Pharmacology has the means in many cases to do this through universal scales of efficacy, affinity, and allosteric modulatory activity. Examples will be given of the application of the Black/Leff operational model for agonism and the functional allosteric model to yield parameters of drug activity that project patterns in tissues beyond the test system. When successful, the parameters obtained function as system-independent descriptions of test molecules suitable for structure-activity relationships for optimization of drug profiles. The synergistic roles of the assay and the models will be highlighted.
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
Loss of APJ-Mediated Beta-Arrestin Signalling Improves High-Fat Diet-Induced Metabolic Dysfunction, but Does Not Alter Cardiac Function in Mice
Liaoyuan Hu, PhD, Scientific Director, in vitro GPCR Pharmacology, Amgen Asia R&D Center
To elucidate the contribution of APJ/beta-arrestin signalling, we generated a transgenic mouse harbouring a point mutation (APJ I107A) that maintains full G protein activity, but fails to recruit b-arrestin following receptor activation. APJ I107A-mutant mice did not alter cardiac function at rest, following exercise challenge or in response to pressure overload-induced cardiac hypertrophy. Additionally, APJ I107A mice have comparable body weights, plasma glucose, and lipid levels to WT mice when fed a chow diet. However, APJ I107A mice showed significantly lower body weight, blood insulin levels, improved glucose tolerance, and greater insulin sensitivity when fed a high-fat diet. Furthermore, loss of APJ b-arrestin signalling also affected fat composition and the expression of lipid metabolism-related genes in adipose tissue from high-fat fed mice. Taken together, our results suggest that G protein-biased APJ activation may be more effective for certain disease indications given that loss of APJ-mediated, b-arrestin signalling appears to mitigate several aspects of diet-induced metabolic dysfunction.
5:30 Talk Title to be Announced
Jean-Philippe Fortin, PhD, Associate Research Fellow – Group Head, Molecular and Cellular GPCR Pharmacology, Pfizer Inc.
6:00 Presentation to be Announced
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
7:30 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
Huixian Wu, PhD, Principal Scientist & Lab Head, Structural Biology, Pfizer Inc.
8:45 CryoEM for Membrane Proteins
Seungil Han, PhD, Associate Research Fellow, Structure Biology & Biophysics, Pfizer Global R&D Groton Labs
This talk will describe applications of cryo-EM to membrane proteins to enable drug discovery. The prospects of studying large disease-relevant macromolecular complexes without having to generate a single crystal are very appealing, and cryo-EM is becoming a part of lead generation in more and more research departments. The introduction of direct electron detectors, the resolution and range of biological molecules amenable to single particle cryo-EM, have enabled this.
Beyond Soluble Targets: Applying CETSA® to Multi-Pass Transmembrane Proteins
Aarti Kawatkar, Senior Scientist, Chemical Biology & Proteomics, AstraZeneca Pharmaceuticals
Demonstration of target binding is a key requirement for understanding the mode of action of new therapeutics. The cellular thermal shift assay (CETSA) has been introduced as a powerful label-free method to assess target engagement in physiological environments. Here, we present the application of live-cell CETSA to different classes of integral multi-pass transmembrane proteins using three case studies: the first showing a large and robust stabilization of the outer mitochondrial five-pass transmembrane protein TSPO; the second being a modest stabilization of SERCA2; and the last describing an atypical compound-driven stabilization of the GPCR PAR2. Our data demonstrated that using modified protocols with detergent extraction after the heating step, CETSA can reliably be applied to several membrane proteins of different complexity. By showing examples with distinct CETSA behaviors, we aim to provide the scientific community with an overview of different scenarios to expect during CETSA experiments, especially for challenging, membrane-bound targets.
NMR and Weak Affinity Chromatography for Small-Molecule and Fragment Screening against GPCRs
Isabelle Krimm, PhD, Principal Investigator, Biomolecular Department, University of Lyon, CNRS
G protein-coupled receptors (GPCRs), which constitute the largest family of proteins targeted by approved drugs, still represent a huge opportunity to develop new drugs for “old” targets or orphan receptors. Significant progresses have been made in the field of fragment screening against those challenging membrane proteins. Recent results obtained with the adenosine receptor using NMR and Microscale thermophoresis (from NanoTemper Technologies) will be discussed.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
10:55 Talk Title to be Announced
David J. Wasilko, Senior Scientist, PGRD Groton Labs, Pfizer Global R&D Groton Labs
11:25 Presentation to be Announced
11:55 Sponsored Presentation (Opportunity Available)
12:25 pm 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
1:55 GPCR Heteromers as Targets for Drug Development
Ajay S. Yekkirala, PhD, Co-Founder & CSO, Blue Therapeutics
GPCRs, over the past two decades, have been shown to form higher-order physical complexes termed homomers (complexes of similar receptors) or heteromers (complexes of different receptors). The discovery of these receptor complexes has provided a new paradigm, as previous GPCR drug discovery efforts have been focused only on monomeric receptors. The goal of Blue Therapeutics is to utilize our deep knowledge in GPCR biology and develop potent analgesics that lack addictive potential. Opioids are the standard of care for treatment of moderate to severe pain, but their widespread use has caused a national health crisis centered on prescription opioid abuse, misuse, and addiction. To tackle this, we are currently advancing our lead molecule, Blue181 - a selective activator of mu-kappa opioid receptor heteromers - as a non-addictive, non-narcotic pain therapeutic through IND studies. In this presentation, Dr. Yekkirala will describe efforts on the development of Blue181 as a case study on utilizing GPCR heteromer biology for targeted drug development.
Spatial Programming of G Protein-Coupled Receptor Signaling: Applications to Sex, Drugs and... Food
Aylin C. Hanyaloglu, PhD, Reader in Cell Biology & Research Lead, Metabolism, Digestion & Reproduction, Imperial College London
Our models of G protein-coupled receptor (GPCR) signaling have evolved from cell surface receptors activating a single specific pathway in a linear fashion, to one that is highly complex, exhibiting extensive signal crosstalk and diversity via a number of mechanisms. Untangling the receptor signaling wires to understand how cells decode this complexity into downstream specific responses remains a current outstanding question. This question has driven research into how membrane trafficking, a system deeply integrated with cell signaling, not only regulates signal diversity, but also signal specificity. Studies over the past decade have demonstrated that membrane trafficking of GPCRs is critical for spatial and temporal control of signaling by directly facilitating G protein signaling from distinct intracellular compartments, including endosomes. Our studies with the gonadotrophin hormone receptors, key in reproduction and pregnancy, have revealed that GPCR activity can be spatially regulated at a complex multi-endosomal level through the identification of a new intracellular compartment, the very early endosome (VEE). In this session, I will discuss how different GPCRs, not only important in reproduction but also in carbohydrate sensing in the gut, employ this trafficking system to create highly regulated and specific signaling profiles for pleiotropically coupled GPCRs, and the physiological impact of such 'location-bias'. Application of these evolving models to therapeutic strategies suggests new mechanisms that could be exploited in GPCR-directed pharmacotherapy.
2:55 Dissecting Molecular Recognition Mechanisms of GPCR Phospho-Barcodes by Arrestin
Jinpeng Sun, PhD, Professor and Chair, Biochemistry and Molecular Biology, Shandong University School of Medicine; Joint Professor, Peking University
G protein-coupled receptors are important transmembrane proteins which account for more than 30% of direct clinical drug targets. Two main signaling pathways, either mediated by different G protein subtype or arrestins, underlie most of 800 GPCR functions in human genome. Selective ligands targeting to one of the G protein- or arrestin-signaling through specific receptor, which is also called biased ligands, may have beneficial effects and delete the unwanted side effects compared with traditional full agonists or antagonists.
Recent structural studies unveiled that both receptor seven transmembrane core and phospho-C-tail engaged with arrestin interactions. Using unnatural amino acid incorporation and genetic expanding technologies, combined with biochemical and crystallographic approaches, we have provided direct experimental evidences that the receptor phosphorylation barcodes in their C-tails could be read by the phospho-pattern readers located in the arrestin, which is the combination of the phosphoate or negative-charged amino acids-binding sites. Binding of each site allosterically produced unique arrestin conformations and correlated to selective arrestin downstream functions. Our results indicated that operation of receptor phospho-barcode could be an important strategy to modulate selective receptor functions, serving as an important aspect for developing biased receptor agonists as new therapies.
Targeting and Exploring the Sodium-Binding Pocket of the μ-Opioid Receptor
Abdelfattah Faouzi, PhD, Postdoctoral Fellow, Clinical Pharmacology, Washington University School of Medicine
For centuries, opioids have been used in the field of pain management, but are now considered a major public health concern, especially in the U.S. Most of the issues arise from our inability to efficiently target the different subtypes of opioid receptors and to trigger a specific functional response correlating with a safe analgesic effect.
These opioid receptors are part of the GPCRs family, which is known to share structural homology across different subfamilies and to mediate pain relief through both the central and the peripheral nervous systems. Recently, the publication of the crystal structures of several GPCRs and opioid receptors have shed light on the presence of allosteric-binding pockets, which are gaining momentum as potential novel alternatives to current therapeutic strategies. We hypothesized that targeting an allosteric site could potentially allow for receptor-functional selectivity and improve the overall side effects profile. More precisely, one site known as the Na+ binding pocket has been identified as critical for GPCR function and to be the center of the functional mechanism, with several bias switches characterized in the pocket residues (Katritch et al., Trends Biochem Sci. 2014).
In this work, we now report the structure-based rational drug design of bitopic ligands targeting the Na+ pocket of mu (MOR) and kappa opioid receptors (KOR). Our novel bitopics show high affinity, subtype selectivity, G protein-biased agonism, and analgesia in mice. Single-amino-acid mutagenesis in the Na+ binding pocket resulted in diminished functional potency of our ligands, thus validating allosteric site targeting. Together, our results suggest the possibility of achieving subtype selectivity and identification of an additional subpocket in both MOR and KOR to reduce ßarrestin-2 recruitment by targeting an allosteric pocket in the opioid receptors. The highly conserved constitution of the Na+ binding pocket opens the opportunity for rational discovery of new GPCR modulators with desired functional, and potentially therapeutic, profiles for opioids, as well as other class A GPCRs.
3:55 Close of Conference