GPCR-Based Drug Discovery

- GPCR基礎的新藥發現 -

G protein-coupled receptors (GPCRs), which relay chemical signals such as hormones from outside to the inside of cells, are the targets of approximately a third of the medicines on the market today. However, many of the GPCR-acting medicines were discovered decades or more ago, without today’s more detailed knowledge about and tools for working with GPCRs. The receptors span the membrane seven times, thus are challenging to solubilize and study in vitro. Recent biophysical advances though have bypassed some of the membrane-embedded challenges and enabled GPCR structural insights and spurred new screening applications. The receptors’ signaling complexities due to their ability to couple to a variety of G proteins (biased signaling) are also now more understood and capitalized upon to design more selective drugs. CHI’s well-established GPCR-Based Drug Discovery conference will continue to convene prominent scientists in both academics and industry to share and discuss the latest advances in applied GPCR research ranging from new screening assays and biophysical techniques, to structure-based drug development to medicinal chemistry optimization case studies to examples of GPCR-targeted compounds in development.

Final Agenda

Thursday, September 27

11:50 am Conference Registration Open

12:20 pm Plenary Keynote Program

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

GPCR Structures And Targeted Drug Design Implications

2:45 Welcome Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks

Dean G. Brown, PhD, Director of External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

2:55 Structural Pharmacology of GPCRs in Asthma and Structure-Based Drug Development

Cheng Zhang, PhD, Assistant Professor, Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine

We present a series of crystal structures of two chemoattractant GPCRs, the C5aR and the CRTH2, as new targets for anti-inflammatory drugs. The structures reveal the molecular basis for the action of their antagonists including two drug candidates that are currently in the late-stage clinical trials for treating ANCA-associated vasculitis and asthma respectively, and provide new insights into drug development. Based on the structures, we have identified compounds with novel structural scaffolds as potential antagonists of these two receptors, which may lead to new drugs with improved pharmacological properties.

3:25 Apelin Receptor Structure and Signaling

Liaoyuan Hu, PhD, Scientific Director, Discovery Pharmacology, Amgen Asia R&D Center

Apelin receptor (APJ) plays important roles in a variety of physiological processes such as heart contractility, energy metabolism and fluid homeostatic. We will report APJ high resolution crystal structure and molecular mechanism of receptor activation and signaling selectivity. These results shed light on the understanding of the general mechanism of class A receptor activation and functional selectivity, and will facilitate the rational design of novel therapeutics with improved pharmacokinetic and pharmacodynamics properties.

3:55 Sponsored Presentation (Opportunity Available)

4:10 Complexity Simplified: Using Smart Drug Discovery Software to Manage Disperse Assay Data

Dan Robinhold, Research Informatics, Collaborative Drug Discovery, Inc.

Research of tomorrow is moving quickly toward a more collaborative, open source and platform-independent environment. CDD Vault (Assay Reg/ELN/Viz) now incorporates “BioAssay Express” that utilizes machine learning to scan and catalog libraries of human-readable assay text into computer-readable format to better access private, collaborative and public assay data.

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

New GPCR-Targeted Assays And Compounds

5:00 Identification and Optimization of a CGRP Receptor Antagonist of Novel Chemotype

Brendan Crowley, PhD, Associate Principal Scientist, Neuroscience, Merck Research Labs

I describe our strategy to rapidly evolve a series of CGRP receptor antagonists utilizing physical property, ligand efficiency, and diversity-guided iterative library design as well as evidence that these molecules make novel interactions in the binding site (from receptor mutagenesis, X-ray crystallography, and NMR data). I also discuss lead optimization efforts that led to an advanced candidate with high affinity for the receptor, potent in vivo activity, good off-target selectivity, and a low potential human dose.

5:30 TruPath: An Open-Source Platform for Comprehensive Screening of GPCR Signal Transduction Pathways

Ryan T. Strachan, PhD, Research Assistant Professor, Pharmacology, University of North Carolina – Chapel Hill

Our understanding of G Protein-Coupled Receptor (GPCR) signaling remains incomplete and likely conceals therapeutically useful bias. Here we present an open source, optimized BRET-based Transducer Pathway screening platform (dubbed ‘TruPath’) that measures activation of 18 different G-protein signaling pathways. When combined with our GPCRome library, TruPath enables potency and efficacy profiling for both established (e.g., opioid) and understudied (e.g., MRGPRX2) receptors and their ligands, thereby revealing the full extent of transducer promiscuity and bias. We hope that such a panoramic understanding of GPCR signaling reveals new biology and therapeutic strategies.

6:00 Exploration of Endosomal GPCR Signaling Using Electron Microscopy

Alex Thomsen, PhD, Assistant Professor, Department of Surgery, Columbia University

We recently demonstrated that a class of GPCRs promotes endosomal signaling by forming “megaplexes” composed of a single GPCR that interacts simultaneously with β-arrestin, which drives the receptor internalization, and G protein, which initiates signaling from internalized compartments. Now we are applying a variety of electron microscopy (EM) and computational methods to obtain high-resolution structural information about the megaplex (cryo-EM), and to visualize GPCR signaling on the endosomal surface within living cells.

6:30 Dinner Short Course Registration

9:30 Close of Day

Friday, September 28

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. Details on the topics and moderators are available on the conference website.


8:30 Chairperson’s Remarks

Lakshmi Devi, PhD, Professor, Department of Pharmacology, Mount Sinai School of Medicine

8:35 FEATURED PRESENTATION: Mu Opioid Receptor Pharmacology: A Window into Another Dimension of GPCR Function

Gavril_PasternakGavril Pasternak, MD, PhD, Chair and Professor of Neurology, Neuroscience, Pharmacology and Psychiatry, Weill Cornell Medical College; Laboratory Head, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center

The mu opioid receptor Oprm1 is a member of the G-protein coupled receptor family. First demonstrated in 1973, it led to the discovery of the endogenous opioids and the ‘sodium effect’ in which sodium ions allosterically transition receptors between agonist and antagonist conformations – now established with most GPCRs. Cloning the receptor uncovered a vast array of Oprm1 splice variants, including an atypical target capable of eliciting analgesia without the side effects associated with classical opioids.

9:05 GPCR Dimerization and Impact on Drug Discovery

Lakshmi Devi, PhD, Professor, Department of Pharmacology, Mount Sinai School of Medicine

Studies in Dr. Lakshmi Devi’s laboratory aim at unraveling the molecular mechanisms of signal transduction mediated by G-protein coupled receptors (GPCRs) and their regulation in health and disease. Recent studies have focused on the identification of compounds targeting opioid receptor heteromers as well as ligands targeting recently deorphanized hypothalamic neuropeptide GPCRs. This presentation will focus on different approaches used in novel ligand identification for the treatment of pain and addiction.

9:35 Angiotensin Receptor Structure and Implications for Biased Signaling

Laura M. Wingler, PhD, Postdoctoral Researcher, Howard Hughes Medical Institute, Lefkowitz Lab, Department of Medicine, Duke University Medical Center

The angiotensin II type 1 receptor is a premier model system for studies of biased agonism in GPCRs, as it has both Gq-biased and β-arrestin-biased agonists that have been exceptionally well characterized. Here we use multiple structural techniques to elucidate the distinct angiotensin receptor conformations stabilized by functionally diverse ligands. Our findings suggest mechanisms by which biased agonists induce the receptor to couple selectively to particular transducers and achieve their different biological profiles.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

Receptor Kinetics And Allosteric Modulation

10:45 FEATURED PRESENTATION: Receptor Kinetics for Probing Allosteric Modulation and Biased Signaling

Terry_KenakinTerry Kenakin, PhD, Professor, Department of Pharmacology, University of North Carolina School of Medicine

I will compare the muscarinic receptor Gq protein activation profiles of five exemplar molecules (slow binding agonists, partial agonists, inverse agonists, PAM-Agonists and Beta-PAMs) in calcium and IP1 assays to illustrate how quantitative comparisons to pharmacological models can both identify mechanisms of action and also convert descriptive findings to predict data for therapeutic systems. Using these models optimally allows the identification of consistent and simple scales of activity that can guide medicinal chemistry.

11:15 Drug-Target Binding Kinetics - A Case for GPCRs

Laura Heitman, PhD, Associate Professor, Research Division of Drug Discovery and Safety, LACDR, Leiden University

The success rate of a candidate drug moving through the clinical development phase is disappointingly low despite the fact that properties of drug candidates for a given therapeutic target are mostly optimized with respect to standard pharmacological parameters of affinity, potency and intrinsic activity. Determining drug target binding kinetics, next to traditional potency measures, may increase the rate of success. Our work provides new insights in ligand-GPCR interactions and underlines the importance of measuring binding kinetics of both drug candidates and competing endogenous ligands.

11:45 Sponsored Presentation (Opportunity Available)

12:15 pm Session Break

12:25 Luncheon Presentation to be Announced

Lisa Minor, Scientific Consultant, Business Development, Multispan, Inc.

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

Biophysical Approaches

1:55 Chairperson’s Remarks

Brian J. Murphy, PhD, Director, Metabolic Disease Biology, Bristol-Myers Squibb Co.

2:00 Discovery of Small Molecule Protease-Activated Receptor 2 (PAR2) Antagonists Using a Stabilized GPCR, Fragment-Based Lead Generation and DNA-Encoded Library Screening

Dean G. Brown, PhD, Director of External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

We employed two screening strategies to identify antagonists at protease activated receptor (PAR2), one being a DNA-encoded library screen on PAR2 and the second a fragment screen using a stabilized PAR2 GPCR receptor. From these efforts, we identified two lead series of compounds, each of which bind to distinct and previously unknown allosteric sites. These results illustrate the power of integrating stabilized GPCR technologies into established screening paradigms.

2:30 Synergizing Applications of Biophysical Methods for Better Lead Generation

Pedro Serrano, PhD, Principal Scientist, Structural Biology and Biophysics, Takeda SD

3:00 Characterization of Wild Type GPCRs Using Surface Plasmon Resonance

Iva Navratilova, PhD, Staff Scientist, Department of Molecular Biology, University of Dundee

Expressing, purifying and analysing membrane proteins using SPR is routinely challenging. In this presentation, we will present our latest results demonstrating a scalable method for the successful development of SPR assays for a wide range of wild-type GPCRs. The SPR assays can be exploited for fragment screening and kinetic characterization to discover novel ligands.

3:30 Nanodiscs for Membrane Protein Drug Discovery Applications

Nasr Mahmoud, PhD, Postdoctoral Fellow, Laboratory of Gerhard Wagner, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

We present a method for manufacturing membrane bilayer nanodiscs encircled by DNA scaffold or covalently circularized Apolipoprotein A1 variants. We are able to extend the size of nanodiscs up to 90 nm in diameter. Furthermore, we demonstrate the potential use of these nanodiscs as model membranes to study virus entry. Finally, we demonstrate the potential use of these newly engineered nanodiscs in GPCR and antiviral drug discovery.

4:00 Close of Conference


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