GPCR-Based Drug Discovery


( GPCR基础的药物发现 )

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.

Choose 2 Short Courses and 2 Conferences/Training Seminars
September 16 Pre-Conference Short Course: SC1: Immunology Basics: Focusing on Autoimmunity and Cancer
September 17-18 Training Seminar: TS1: Targeting GPCRs for Drug Discovery
September 18 Dinner Short Course: SC8: GPCR Structure-Based Drug Discovery
September 18-19 Conference: GPCR-Based Drug Discovery

Final Agenda


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

Bouvier_MichelThis 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, Baylor College of Medicine

-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

Anjan Chakrabarti, Vice President, Discovery Chemistry, Syngene International Ltd

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

Player_MarkMark 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

Griffith_DavidDavid 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 Enabling Drug Discovery with Multispan

Lisa Minor, Scientific Consultant, Multispan, Inc.

The path to successful drug discovery requires 1) a validated target, 2) assays accurately measuring the specific target, and 3) assays run reproducibly and robustly. This presentation will demonstrate how Multispan can uniquely empower your drug discovery efforts. We provide fully validated cells expressing your target along with a battery of well characterized MultiScreen™ assays for conducting your primary and secondary screens in our Bay Area laboratory.  Our vast attention to detail and cellular pharmacology helps to ensure your project's success and shorten your timeline.

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

5:00 Signaling Bias of a Novel LPAR1 “Antagonist” Lead Molecule and Implications for Drug Discovery

Rives_Marie-LaureMarie-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 fibrotic diseases. 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?

Sage_CarltonCarleton 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

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

The success rate of a candidate drug moving to the pre-clinical development phase is disappointingly low, mainly due to lack of clinical efficacy. Novel drug discovery concepts (e.g. target binding kinetics and allosteric modulation) might offer a different mechanism of action for drug candidates.  Specifically, today’s talk will show new avenues for CCR2, and GPCR small molecule drug discovery.

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

9:30 Close of Day


7:00 am Registration Open

7:30 Interactive Breakfast Breakout Discussion Groups - View All Breakouts

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.

Biased Signaling

Moderator: John Janetzko, PhD, Damon Runyon Postdoctoral Fellow, Kobilka Lab, Department of Molecular and Cellular Pharmacology, Stanford University

  • Structural determinants of ligand bias
  • The role of GRKs in biased signaling
  • Cryo-EM of GPCR complexes and its role in drug discovery
  • How can academic research help the development of new drugs?

GPCR Targeted Lead-Development Challenges

Moderator: Phil Carpino, PhD, Scientific Director, Discovery Chemistry, Janssen Research & Development

  • Untangling biased signaling
  • Comparing various cell-based screens
  • Medicinal chemistry challenges

GPCR-Ligand Binding Kinetics

Moderator: Sam Hoare, PhD, Founder, Pharmechanics LLC

  • Compound residence time vs. compound in vivo efficacy
  • Off rate and duration of action
  • Kinetic artifacts in SAR assays

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

Michael Fossler, PharmD, PhD, FCP, Vice President, Clinical Operations and Quantitative Sciences, 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

Bahl_ChristopherChristopher 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

Maeda_ShojiShoji 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

Hebert_TerryTerry 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

Rascha_SebastianSebastian 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

InterAx 12:45 Luncheon Presentation: Integrating Experimental and Computational Pharmacology for Intelligent GPCR Drug Candidate Selection

Martin Ostermaier, PhD, CEO, InterAx Biotech AG

InterAx built a computational tool to integrate theoretical knowledge with experimental data of GPCR-mediated trafficking events. As a result, deeper mechanistic insights into the dynamic cellular system are achievable. Such mathematical models allow to predict experimental outcomes and deliver novel insights into drug actions on GPCRs. As an example, our predictive model allowed us to discriminate 17 marketed asthma drugs for their duration of action. This technology is currently applicable to discovery programs on GPCRs.

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)

Wasnaire_PierrePierre 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 Structural Insights into GPCR Recognition by Arrestin

John Janetzko, PhD, Damon Runyon Postdoctoral Fellow, Kobilka Lab, Department of Molecular and Cellular Pharmacology, Stanford University

While there is a wealth of structural information pertaining to the basis of G protein-receptor interactions, there exists no structure of a non-rhodopsin GPCR in complex with arrestin. Using cryo-electron microscopy we obtained a structure of the neurotensin type I receptor (NTSR1) in complex with arrestin 2. This structure reveals how the receptor is engaged by arrestin, how phosphorylation of the receptor might regulate arrestin recruitment and activation and how the plasticity of the interactions formed between the two enable arrestin to recognize a large set of diverse GPCRs.

3:40 Surface Plasmon Resonance Microscopy for GPCRs

Wu_ShijieShijie 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

* 活动内容有可能不事先告知作更动及调整。

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