GPCR-Based Drug Discovery


G-protein coupled receptors (GPCRs) play roles in many physiological processes and have therefore been the target of medical therapeutics for decades. Their complexities in signaling, however, are still being unraveled and starting to be exploited for more targeted therapies. For example, therapeutics with fewer side effects are being sought by finding biased ligands of specific GPCRs that will activate or block the pathway of medical interest while not initiating less desirable signaling cascades that the GPCR also controls. Progress in biophysical techniques and cryo-electron microscopy have also aided targeted drug discovery against GPCRs by enabling biosensor-based screens or by helping elucidate structural features of GPCRs that guide structure-based drug design. At CHI’s well-established GPCR-Based Drug Discovery conference, join colleagues and experts in the GPCR field who hail from both academics and industry to review advances in the field and discuss cutting edge topics impacting drug development against this very medically relevant class of drug targets.

Final Agenda

Wednesday, September 18

10:50 - 11:50 BRIDGING LUNCHEON PANEL DISCUSSION: GPCRs: Leveraging Years of Data for Transformative Drug Discovery

This 1-hour panel moderated by Michel Bouvier, PhD, Principal Investigator & CEO, Institute for Research in Immunology and Cancer (IRIC) and Professor, Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal will feature two talks related to new horizons in GPCR drug discovery. The talks will be followed by a question and answer session.

-GPCR Mutations: Towards a More Personalized Drug Discovery

Olivier Lichtarge, MD, PhD, Molecular and Human Genetics, Computational and Integrative Biomedical Research Center

-Virtual Screening: A Post-Structural Era

John Irwin, PhD, Adjunct Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco

11:20 Conference Registration Open

11:50 Session Break

Click here for full abstracts.

12:20 pm Event Chairperson’s Opening Remarks

An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute


12:30 Plenary Keynote Introduction

12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells

David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University



1:20 PROTACs: Past, Present, and Future

Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University



2:00 Close of Plenary Keynote Program

2:00 Dessert Break in the Exhibit Hall with Poster Viewing

GPCRs In Disease

2:45 Organizer's Welcome Remarks

2:50 Chairperson’s Opening Remarks

Ajay Yekkirala, Co-Founder and CSO, Blue Therapeutics

2:55 Design and Preclinical Profile of a GPR40 Superagonist

Mark R. Player, MD, PhD, Senior Scientific Director & Fellow, Discovery Chemistry, Janssen Pharmaceutical Research & Development

Full agonists of GPR40 exhibit superior glucose lowering to partial agonists in pre-clinical species due to increased insulin and GLP-1 secretion, the latter also promoting weight loss. We have identified a GPR40 superagonist which displayed excellent in vitro potency and superior efficacy in the Gas-mediated signaling pathway. Design and preclinical efficacy (human islets, oGTT and weight loss in DIO mice) and safety data (DILI-derisking, pancreatic insulin/proinsulin after compound rechallenge in Wistar rats) will be presented.

3:25 GLP1-R Agonist

David A. Griffith, PhD, Research Fellow, Medicinal Chemistry, Pfizer Global R&D

Glucagon-like peptide-1 receptor (GLP-1R) agonists comprise a growing class of agents that deliver unprecedented efficacy in diabetes. We will report on a program to identifyan oral, small molecule GLP-1 receptor agonist for the treatment of diabetes. An innovative hit identification strategy provided weak leads that were progressed through structure-activity exploration to achieve drug-like potency and ADMEattributes. This presentation will disclose the discovery of the oral small molecule GLP-1R agonist PF-06882961, including emerging human pharmacokinetic data.

3:55 Talk Title to be Announced

Lisa Minor, Scientific Consultant, Multispan, Inc.

4:10 Sponsored Presentation II (Opportunity Available)

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

5:00 LPAR1 Tool Compound with Signaling Bias Properties

Marie-Laure Rives, PhD, Senior Scientist, Molecular and Cellular Pharmacology, Lead Discovery, Janssen Research & Development

Lysophosphatidic acid (LPA) is a bioactive lipid and pro-fibrotic agent acting through LPA receptors: LPAR1 - 6. A wealth of preclinical data has revealed the relevance of LPAR1 in the development of kidney fibrosis. We have identified a new LPAR1 allosteric antagonist that shows promising selectivity. However, this compound and its analogs show intriguing signaling bias properties whose physiological consequences are still unknown and under investigation.

5:30 GPR84: Can Context-Dependent Signaling Inform Therapeutic Direction?

Carleton Sage, PhD, Vice President, Computational Sciences, Beacon Discovery

GPR84 is an inflammation-related orphan G Protein-Coupled GPCR. Expression analysis suggests that modulation of GPR84 could be valuable for inflammation related diseases such as Crohn’s disease, IBD, or idopathic pulmonary fibrosis, but thus far agonists have proven unsuccessful in clinical trials. New observations of signaling in immune cells suggest an explanation and a path forward.

6:00 Drug-Target Binding Kinetics – Implications for Insurmountable Antagonism at GPCRs

Laura H. Heitman, PhD, Associate Professor for Molecular Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University

6:30 Dinner Short Course Registration
Click here for details on short courses offered.

9:30 Close of Day

Thursday, September 19

7:00 am Registration Open

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

Biased Agonists And Allosterism

8:40 Chairperson’s Remarks

Huixian Wu, PhD, Principal Scientist, Structural and Molecular Sciences, Discovery Sciences, Pfizer, Inc.

8:45 FEATURED PRESENTATION: Bias and Beyond: Challenges and Opportunities in GPCR Drug Development

Ian James, PhD, Associate Director, Clinical Operations, Trevena, Inc.

Oliceridine is a novel investigational G protein-biased ligand at the µ-opioid receptor developed for the management of moderate to severe acute pain. Oliceridine produced differentiated pharmacology in preclinical studies compared to unbiased ligands and maintained a similar profile in the clinic—rapid analgesia with a favorable safety profile with regard to respiratory and gastrointestinal adverse effects compared to morphine. The totality of the data indicate that ligand bias is an important concept in designing new drugs.

9:15 De novo Design of Gα Mimetics: Generalizable Tools for Allosteric Control of G Protein-Coupled Receptors

Christopher D. Bahl, PhD, Head of Protein Design, Institute for Protein Innovation

Generalizable tools to stabilize the active conformational state of GPCRs will facilitate protein purification and structure determination, as well as accelerate the engineering of molecules which act as agonists or antagonists. Using de novo protein design, we have developed novel Galpha mimetic proteins that are thermostable, selectively bind to the active state of GPCRs, and can bind to a wide range of different GPCRs.

9:45 Structure-Based Conversion of the Subtype Selectivity of the Muscarinic Toxin

Shoji Maeda, PhD, Senior Postdoctoral Fellow, Kobilka Lab, Department of Molecular and Cellular Physiology, Stanford University

Muscarinic toxin 7 (MT7) is a natural protein toxin produced by green mamba snakes that exclusively binds to muscarinic acetylcholine receptor 1 (M1R) and modulates its function. To understand the molecular mechanism of this strict subtype selectivity and allosteric mechanism, we solved the crystal structure of M1R-MT7 complex. Furthermore, we converted the selectivity of MT7 towards M2R by in vitro engineering. This study suggests the possibility of the three-finger fold as a promising scaffold to target GPCRs.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

Non-Classical Signaling

10:55 Understanding the Consequences of GPCR Dimerization

Terry Hébert, PhD, Professor, Department of Pharmacology and Therapeutics, McGill University

How GPCRs interact with one another remains an area of active investigation. Well-characterized dimers of class C GPCRs such as GABA-B and glutamate receptors are well accepted, but whether this is a general feature of GPCRs is still debated. GPCR oligomers are better imagined as parts of larger metastable signaling complexes. The nature of functional oligomeric entities, stability, kinetic features and structural and functional asymmetries of such metastable entities have implications for drug discovery.

11:25 FEATURED PRESENTATION: Non-Traditional Aspects of Gαs: Interaction with Ubiquitin and Regulation of GPCR Endosomal Sorting

Christine Lavoie, PhD, Professor, Department of Pharmacology and Physiology, University of Sherbrooke

Although Gαs structure has been known for years, we found a novel motif in Gαs that allows its interaction with ubiquitin, a key signal for receptor sorting to the lysosomal pathway. This presentation will cover the new role for Gαs as an integral component of the ubiquitin-dependent endosomal sorting machinery of GPCRs and highlight the dual role of Gαs in receptor trafficking and signaling for the fine-tuning of the cellular response.

CollaborativeDrugDiscovery_New 11:55 Using Smart Drug Discovery Software to Enhance Collaboration and Manage Disperse Assay Data

Robert Thorn, PhD, Customer Engagement Scientist, Collaborative Drug Discovery, Inc.

12:10 pm Machine-Learning & AI-Based Approaches for GPCR Bioactive Ligand Discovery

Sebastian Raschka, PhD, Assistant Professor, Department of Statistics, University of Wisconsin at Madison

This talk will provide an overview of the latest advances for automating the discovery of bioactive ligands using machine learning. Applications include the discovery of a potent GPCR pheromone inhibitor as well as models predicting active and inactive GPCR states by combining machine learning and structural rigidity analysis. Lastly, the talk will conclude with the recent developments in deep learning that are aimed at replacing the need for hand-engineering molecular representations by automatic representation learning.

12:40 Session Break

12:45 Luncheon Presentation: Use of InCELL Pulse™ Cellular Thermal Shift Target Engagement Assays in Early Drug Discovery

Paul Shapiro, PhD, Group Leader, Assay and Product Development, Research and Development Department, Eurofins DiscoverX

A common problem in early target-based drug discovery is the lack of correlation between potencies, or even rank order of potencies, derived from initial biochemical screens and those observed in cellular assays. In phenotypic screening approaches, often the actual drug target is unknown and needs to be identified and proven. Cellular thermal shift assays for target engagement are of increasing interest because they bridge these gaps, however, existing technologies have been cumbersome and low-throughput. InCELL Pulse™, using Eurofins DiscoverX Enzyme Fragment Complementation technology, is a rapid, homogeneous, cell-based assay based on ligand-induced changes in protein thermal stability and is used to study drug-target engagement in live cells. We have successfully applied InCELL Pulse™ to rapidly measure quantitative cellular target engagement potency values for ligands of diverse intracellular protein classes such as kinases, methyltransferases, and hydrolases.

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing

Medicinal Chemistry AND Biophysical Approaches For GPCRs

2:05 Chairperson’s Remarks

Mark R. Player, MD, PhD, Senior Scientific Director & Fellow, Discovery Chemistry, Janssen Pharmaceutical Research & Development

2:10 Lessons Learned from Various GPCR Lead Optimization Projects

Chi Sum, PhD, Senior Research Investigator, Lead Discovery and Optimization, Bristol Myers Squibb & Co.

The recent new concepts of GPCR function, including signaling bias, allosteric, kinetics, and receptor trafficking, have provided an important frame of reference for GPCR Drug Discovery. Recognizing these pharmacological properties has become fundamental for a successful campaign. Here, we present some case studies on how these principles operate directly or indirectly to influence lead optimization effort.

2:40 First Orally Bioavailable Antagonist of the Neuropeptide Y Receptor 2 (NPY2R)

Pierre Wasnaire, PhD, Senior Scientist, Pharmaceuticals R&D, Bayer AG

Autonomic imbalance with increased sympathetic activity and withdrawal of vagal activity is associated with increased mortality both after myocardial infarction (MI) and in heart failure (HF). Neuropeptide Y (NPY) is suggested to be a key link between enhanced sympathetic and decreased vagal activity in autonomic imbalance in HF. NPY receptor 2 (NPY2R) antagonism seems attractive for the treatment of autonomic imbalance by restoring vagal activity in HF patients and patients post-MI. After high-throughput screening and medicinal chemistry optimization we found new, potent and selective NPY2R antagonist, showing suitable DMPK and safety profiles.

3:10 Nanodiscs for GPCRs

Daniel Oprian, PhD, Professor, Biochemistry, Brandeis University

3:40 Surface Plasmon Resonance Microscopy for GPCRs

Shijie Wu, PhD, Application Scientist, Biosensing Instrument

One of the most recent significant biophysical advances to study GPCR binding properties is Surface Plasmon Resonance Microscopy (SPRM), a powerful technique that simultaneously visualizes cellular structures and measures molecular binding interactions of membrane proteins label-free, in vitro and in real time. With this award-winning biosensor technique, the measurement of phenotypical changes of the cell via bright field and binding affinity and kinetics of GPCR targets via SPR can be done. In this presentation, we will review the principles behind SPRM and show application examples of binding affinity and kinetics of multiple whole cells as well as localized responses on a single cell.

3:55 Close of Conference