Cambridge Healthtech Institute’s 15th Annual

GPCR-Based Drug Discovery

Targeting G Protein-Coupled Receptors for New Therapeutic Options

September 17 - 18, 2020 ALL TIMES EDT

G protein-coupled receptors (GPCRs) have been a medically relevant drug target for decades because of the central roles they play in a variety of physiological processes. At least 25% of the drugs on the market achieve their effect via GPCRs. The receptors are a challenging target class to work with, however, because they are embedded in the membrane and have complex signaling properties (a single type of GPCR can couple to and activate or inhibit a variety of G proteins). Recent advances in biophysical screening approaches though are facilitating GPCR-targeted drug discovery. Cryo-electron microscopy and X-ray crystallography improvements have also aided drug discovery against GPCRs. Join us at the 15th Annual GPCR-Based Drug Discovery conference, part of Discovery on Target, to hear about examples of early drug discovery work with newer approaches and GPCR-targeted candidates progressing in the pipeline.

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

ENGAGING GPCRs

2:05 pm 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 HM2K (HeteroMer-Mu-Kappa) 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.

2:25 pm

Targeting and Exploring the Sodium-Binding Pocket of the μ-Opioid Receptor

Abdelfattah Faouzi, PhD, Postdoctoral Fellow, Clinical Pharmacology, Washington University School of Medicine

The understanding and modulation of the opioid receptors' pharmacological profiles is still considered as one of the highest priorities in order to develop safer pain-relieving agents. We used a structure-based approach to develop a small library of selective G protein-biased agonists, which aimed at targeting simultaneously both the orthosteric and allosteric sodium-binding pocket site of the 
μ-opioid receptor. Structure activity relationships were validated using mutational and structural analysis.

2:45 pm

Discovery of PF-06882961: A Potent, Orally Bioavailable Small Molecule Agonist of the GLP-1 Receptor

Jean-Philippe Fortin, PhD, Associate Research Fellow – Group Head, Molecular and Cellular GPCR Pharmacology, Pfizer Inc.

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the discovery and characterization of PF-06882961, an effective and orally bioavailable small molecule GLP-1R agonist drug candidate. This work opens the door to a new era of oral small molecule therapies that target the GLP-1R pathway for metabolic health.

Lisa Minor, PhD, Scientific Consultant, Multispan, Inc.

To advance early stage drug discovery, developing relevant HTS assays for the target is paramount. It requires speed, robustness and reproducibility.  For such purpose, as a CRO and research tools provider, we at Multispan have built a long successful track record in assay development, high-throughput screening and cell engineering.  In this presentation, we will share details on our approach and introduce our new efforts in BacMam and HSV viral delivery of MultiScreen™ Arrestin-Sensor for native GPCRs, CRISPR knock-out and SARS-CoV2 assays.  We will also share a few case studies highlighting how we helped our partners accomplish their project goals by running projects in our hands, driving chemistry efforts with high quality and reliable data generated at Multispan.

3:25 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Ajay S. Yekkirala, PhD, Co-Founder & CSO, Blue Therapeutics
Panelists:
Abdelfattah Faouzi, PhD, Postdoctoral Fellow, Clinical Pharmacology, Washington University School of Medicine
Jean-Philippe Fortin, PhD, Associate Research Fellow – Group Head, Molecular and Cellular GPCR Pharmacology, Pfizer Inc.
Lisa Minor, PhD, Scientific Consultant, Multispan, Inc.
3:45 pm Happy Hour - View Our Virtual Exhibit Hall
4:15 pm Close of Day

Friday, September 18

GPCR SIGNALING COMPLEXITIES

10:00 am

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.

10:20 am

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.

10:40 am 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.

Lei Jin, COO, Wuxi Biortus Biosciences Co., Ltd.

G protein-coupled receptors (GPCRs) are important drug targets. For GPCR drug discovery, protein production and 3D molecular structures of GPCRs are essential. I will share strategies and tricks which we have been using for GPCR protein production and introduce the emerging atomic-resolution cryoEM approach for GPCR structure determination.

11:20 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Matthew T. Eddy, PhD, Assistant Professor, Chemistry, University of Florida, Gainesville
Panelists:
Liaoyuan Hu, PhD, Scientific Director, in vitro GPCR Pharmacology, Amgen Asia R&D Center
Aylin C. Hanyaloglu, PhD, Reader in Cell Biology & Research Lead, Metabolism, Digestion & Reproduction, Imperial College London
Jinpeng Sun, PhD, Professor and Chair, Biochemistry and Molecular Biology, Shandong University School of Medicine; Joint Professor, Peking University
Lei Jin, COO, Wuxi Biortus Biosciences Co., Ltd.
11:40 am Coffee Break - View Our Virtual Exhibit Hall

GPCR STRUCTURAL AND BIOPHYSICAL TOOLS

11:55 am

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.

12:15 pm

Structural Basis for Chemokine Receptor CCR6 Activation by the Endogenous Protein Ligand CCL20

Jon Wasilko, Postdoctoral Fellow, Discovery Sciences, Medicine Design, Pfizer Inc.

Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors which belong to the G protein-coupled receptor (GPCR) superfamily. Despite the substantial progression of our structural understanding of GPCR activation by small molecule and peptide agonists, the molecular mechanism of GPCR activation by protein agonists remains unclear. Here, we present a 3.3-Å cryo-electron microscopy structure of the human chemokine receptor CCR6 bound to its endogenous ligand CCL20 and an engineered Go. CCL20 binds in a shallow extracellular pocket, making limited contact with the core 7-transmembrane (TM) bundle. The structure suggests that this mode of binding induces allosterically a rearrangement of a noncanonical toggle switch and the opening of the intracellular crevice for G protein coupling. Our results demonstrate that GPCR activation by a protein agonist does not always require substantial interactions between ligand and the 7TM core region.

12:35 pm

Enabling Cellular Target Engagement Assays for Membrane 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.

12:55 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Huixian Wu, PhD, Structural Biology Lab Head, Discovery Sciences, Medicine Design, Pfizer Worldwide Research & Development
Panelists:
Isabelle Krimm, PhD, Principal Investigator, Biomolecular Department, University of Lyon, CNRS
Jon Wasilko, Postdoctoral Fellow, Discovery Sciences, Medicine Design, Pfizer Inc.
Aarti Kawatkar, Senior Scientist, Chemical Biology & Proteomics, AstraZeneca Pharmaceuticals
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: Structural and Biophysical Tools for GPCRs

Huixian Wu, PhD, Structural Biology Lab Head, Discovery Sciences, Medicine Design, Pfizer Worldwide Research & Development

 

  • GPCR crystallography innovations and applications
  • CryoEM insights
  • NMR for GPCRs
  • GPCRs and Nanodiscs

GPCR PHARMACOLOGY

2:00 pm KEYNOTE PRESENTATION:

The Essential Role of Pharmacological Assays and Models in the Lead Optimization Stage of Drug Discovery and LIVE Q&A


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.

2:40 pm Close of Conference





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