2017 Archived Content
G protein-coupled receptors (GPCRs) are targeted by approximately 25-30% of the drugs on the market today which is a testament to the important physiological roles GPCRs play in transducing signals from outside of cells to the inside. However many of the therapeutics now known to act upon GPCRs were actually discovered decades ago before knowledge about their target. This meeting covers the newer era of target-driven drug discovery where the aim is to apply knowledge about GPCR structure and conformation to tailor new drug candidates that bias receptor signaling towards the ‘good’ pathways and away from undesired signaling pathways. Join us at Cambridge Healthtech Institute’s 12th Annual GPCR-Based Drug Discovery conference to discuss and track R&D progress of tackling this complex, membrane-embedded protein class and judge how the significant strides in structural knowledge of various GPCRs, and applications of biophysical techniques, have impacted GPCR-based drug discovery.
Final Agenda
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Tuesday, September 26
7:00 am Registration Open and Morning Coffee
8:00 Welcome Remarks
Anjani Shah, Ph.D., Conference Director, Cambridge Healthtech Institute
8:05 Chairperson’s Opening Remarks
Andrew Alt, Ph.D., Associate Director, Biology, Arvinas
8:10 Mechanistic Insights into Opioid Receptor Function from Molecular Dynamics Simulations
FEATURED PRESENTATION:
Marta Filizola, Ph.D., Professor, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai
Understanding at the molecular level how to fine-tune opioid receptor signaling toward the analgesic pathway and away from those mediating adverse effects is essential for the future discovery of improved opioid-based painkillers for the management of acute and/or chronic pain. I will provide an overview of studies we are carrying out to address this problem using enhanced molecular dynamics simulation strategies and cutting-edge statistical analyses.
8:40 Biased Signaling at μ Opioid Receptor Splice Variants
Ying-Xian Pan, M.D., Ph.D., Laboratory Head, Department of Neurology, Memorial Sloan Kettering Cancer Center
Extensive 3’ alternative splicing of the μ opioid receptor gene (OPRM1) creates multiple C-terminal splice variants that are potentially subjected to biased signaling. We now demonstrate in vitro that several μ agonists display differential β-arrestin 2 or G protein bias against a number of Oprm1 C-terminal splice variants, which correlates with in vivo data using targeted mouse models, providing new insights on GPCR-biased signaling.
9:10 High Resolution Crystal Structure of the Apelin Receptor
Liaoyuan Hu, Ph.D., Scientific Director, Head of Pharmacology, Amgen Asia R&D Center
The apelin receptor (APJ) plays an important role in a wide range of physiological functions and is a potential target for the treatment of a variety diseases. Here we report the high resolution co-crystal structure of APJ in complex with a surrogate peptide agonist. Overall structural features of the complex and detailed peptide/receptor interactions will be discussed.
9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:25 Ozanimod: An S1P1,5R Modulator that Causes Receptor Internalization Resulting in Altered Lymphocyte Trafficking and Amelioration of Inflammation
Julie Selkirk, Ph.D., Associate Director of Cellular & Molecular Biology, Receptos/Celgene
S1P1R is a GPCR expressed on lymphocytes mediating migration out of secondary lymphoid tissues. S1P1R modulators internalize the receptor, sequestering lymphocytes and preventing their migration to inflammation sites. The S1P1,5R modulator ozanimod is in clinical development to treat Multiple Sclerosis and Inflammatory Bowel Disease. This presentation will cover the pharmacological tools we used to identify a safe and effective S1P1,5R modulator and evidence that ozanimod utilizes different residues than FTY720-p in the orthosteric ligand binding pocket.
10:55 Structure of a Family A GPCR with Synthetic Ligands Bound
Adam Weinglass, Ph.D., Director, Screening & Compound Profiling, Merck & Co.
Agonists of GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Pharmacologic studies indicate that partial and full allosteric agonists (AgoPAMs) bind distinct sites on GPR40 eliciting differentiated preclinical efficacy. Here, we present the path to a ternary complex structure with partial and full allosteric agonists bound, and evidence supporting an identified novel, lipid-facing AgoPAM binding pocket.
11:25 Biased and Cell-Specific Agonists of the Heart Disease Target, RXFP1, a Peptide-Targeted GPCR
Ross Bathgate, Ph.D., Head, Neuropeptides Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne
This presentation will discuss peptide mimetic and small molecule development at a complex peptide GPCR, the heart disease target, RXFP1. We have developed a relaxin peptide mimetic with a cell-specific signaling profile and demonstrated that an RXFP1 small molecule agonist is an allosteric biased agonist. This highlights the need to screen GPCR targeted small molecules or biologics in relevant native cell systems for biased and cell-specific signaling.
11:55 Imipridones: A New Class of Anti-Cancer Small Molecules that Selectively Engage GPCRs
Varun Prabhu, Ph.D., Associate Director, Research & Development, Oncoceutics, Inc.
GPCRs are the most commonly exploited target in modern medicine; however, efforts in oncology have been limited. We describe imipridone small molecules with a unique tri-heterocyclic core structure that selectively target GPCRs. Lead candidates were profiled using the DiscoverX GPCR platform and characterized for mechanism of action and anti-cancer efficacy.
12:10 pm Sponsored Presentation (Opportunity Available)
12:25 Session Break
12:35 Luncheon Presentation:
Reaching Beyond Developing Stable GPCR Cell Lines
Lisa Minor, Ph.D., Scientific Consultant, Multispan, Inc.
Developing high quality assays is paramount for lead discovery and optimization screening. Multispan is well known for our deep foundation in generating quality stable GPCR cell lines and conducting functional assays. Our portfolio has expanded by tackling other related topics. We have devoted significant effort in developing signaling and phenotypic assays using endogenous targets such as RXFP1 in THP-1, CGRP receptor (CLR+RAMP1) in SK-N-MC, AMPK in C2C12, and DNA-PK in HELA cell lines. For cross-reactivity counter screens, we have developed specific cell lines and assays for CGRP, AM, and Amylin receptors by studying and overcoming endogenous RAMP expression and designed a 32-GPCR assay panel comprising the most well-characterized CNS and cardiovascular liability targets. In addition to quantifying GPCR expression by radioligand binding, we have also established a FACS-based quantification of surface expression to rank order recombinant clones and benchmark target expression against physiological level in native cells. In this presentation, we will share our recent work and details of these advances.
1:15 Refreshment Break in the Exhibit Hall with Poster Viewing
1:50 Chairperson’s Remarks
Sid Topiol, Ph.D., CSO, 3D-2drug, LLC; Professor and Director, Structural and Computational Drug Discovery, Stevens Institute of Technology
1:55 GPCRs in Immune Evasion of Cancer
Tillmann Michels, Ph.D., Head of Research Group Immune Checkpoint Inhibitors, Laboratory of Phillipp Beckhove, Interventional Immunology, Regensburg Center for Interventional Immunology
Checkpoint blockade has become an important pillar of cancer therapy. We identified GPCRs and their associated signaling as immune inhibitory pathways using high throughput RNAi screening. GPCRs could either affect T cell activity directly by binding or indirectly by altering the balance of tumor-intrinsic Gα signaling. For example, cAMP can be transported into TILs and induce an inhibitory pathway resulting in TCR-associated Lck inhibition.
2:25 Phenotypic Discovery of ONC201 as the First Selective DRD2 Antagonist for Clinical Oncology
Joshua Allen, Ph.D., Vice President, R&D, Oncoceutics
Imipridones are a new class of anti-cancer small molecules that share a unique tri-heterocyclic core structure and selectively engage GPCRs. Experimental GPCR profiling revealed imipridone ONC212 selectively targets orphan GPCR GPR132/G2A at nanomolar concentrations. GPR132 is a stress-inducible orphan GPCR with highest expression in leukemia and shown to be a tumor suppressor in the context of lymphoid leukemogenesis. ONC212 was non-toxic to normal cells at therapeutic concentrations and demonstrated robust in vivo safety/efficacy in leukemia xenograft
2:55 Present and Future Collaborative Innovations within Drug Discovery Informatics
Luke Fisher, Ph.D., Principal Consultant, Collaborative Informatics, Collaborative Drug Discovery
The CDD Vault platform (Activity & Registration, Visualization, Inventory, & ELN) provides an easy, secure way for the collaborative sharing of research data and workflows. Web-based platforms are a natural fit for collaborations due to the economic and design benefits of a single platform that transcends any one organization’s requirements.
3:10 3DM Protein-Family Analysis Platform Applied to the GPCR Protein-Family
Henk-Jan Joosten, Ph.D., CEO, Bio-Prodict
Vast amounts of data are available for protein-families (e.g., sequences, literature, structural-, alignment-, SNP-, mutation-, patent-, binding data). 3DM, a protein-superfamily analysis platform, automatically collects and integrates all data and contains many state-of-the-art analysis tools. 3DM is used by many companies, including large pharma, to guide structure-based drug design.
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
4:05 The Apelin Receptor: Modulating Ligand Structure to Bias Signaling and Impacts on Acute Cardiac Dysfunction
Eric Marsault, Ph.D., Professor, Department of Pharmacology-Physiology, University of Sherbrooke
4:35 Development of GIP Receptor Antagonists to Reveal the Role of GIP in Physiology and Pathophysiological Conditions Like Obesity and T2D
Mette M. Rosenkilde, M.D., Ph.D., Professor, Department of Biomedical Sciences, University of Copenhagen
I will discuss the incretins (that bind to class B GPCRs) and novel data for the production of a GIPR (glucose-dependent insulinotropic polypeptide receptor) antagonist for the treatment of T2D and obesity. I will also compare the action of GIP with that of the other famous incretin hormone, GLP1, for which several therapies have been launched recently.
5:05 Interactive Breakout Discussion Groups
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 below. Please click here for full details on all breakouts.
New Ways to Screen GPCRs
Moderator: Samantha J. Allen, Ph.D., Senior Scientist, Lead Discovery - Screening, Janssen Research & Development
- Physiologically relevant cells and assays
- High-content screening
- Newer assay kits
- Understanding signaling bias
Biophysical Approaches to GPCR Drug Discovery
Moderator: Phillip Schwartz, Ph.D., Senior Scientist, Biophysical Chemistry, Takeda
- Physiological or mimetic, in what matrices should GPCRs be placed for biophysical characterization?
- Promising new technologies to study GPCR-drug interactions
- Fragment screening GPCRs: best methods and practices
Opioid Receptor Targeting
Moderator: Ying Xian Pan, M.D., Ph.D., Laboratory Head, Department of Neurology, Memorial Sloan Kettering Cancer Center
- Which biased ligands show the most promise?
- How to correlate in vitro biased signaling studies with in vivo results?
- How can we integrate structural knowledge into new drug design?
- What are the challenges in designing new biased ligands?
6:05 Welcome Reception in the Exhibit Hall (Sponsorship Opportunity Available)
7:10 Close of Day
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Wednesday, September 27
7:30 am Registration Open and Morning Coffee
8:00 Chairperson’s Remarks
Annette Gilchrist, Ph.D., Professor, Pharmacology, Midwestern University
8:05 Crystal Structure of the GLP-1 Receptor Extracellular Domain in Complex with Exendin-4 and a Nanobody
Xiaomin Chen, Ph.D., Senior Principal Scientist, Structural & Molecular Sciences, Worldwide Research & Development, Pfizer
Glucagon-like peptide 1 receptor is one of the class B GPCR and an important drug target. It has an extracellular domain (ECD) in addition to the seven-transmembrane helices and the primary role of the ECD is to bind to a peptide ligand to position it so that its N-terminus binds to the transmembrane region for its activation. Here we report the crystal structure of the receptor ECD bound to exendin-4 and a nanobody.
8:35 Picking the High-Hanging Fruit: Measuring Biomolecular Interactions of GPCRs Using a Variety of Biophysical Techniques
Phillip Schwartz, Ph.D., Senior Scientist, Structural Biology and Biophysics, Takeda California
Drug discovery efforts are undergoing a renaissance in GPCR-related research as orphan receptors become de-masked and our understanding of how to study these difficult targets improves. Identifying preparations amenable to biophysical characterization is a critical step in pursuing GPCR drug development.
9:05 Improved Candidate Identification & Optimization Using Advanced, Non-viral Cell Engineering
James Brady, Vice President, Technical Applications & Customer Support, MaxCyte, Inc.
Whether developing small molecule drugs or therapeutic antibodies against membrane receptors, cell-based assays play a critical role in identifying and optimizing candidates. This presentation discusses how high-performance cell engineering can significantly improve the relevance and throughput of cell-based assays leading to advancement of higher quality candidates, faster and more cost-effectively.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20 NMR Spectroscopy and Integrative Structural Biology of Human GPCRs
Matthew Eddy, Ph.D., Postdoctoral Fellow, Laboratory of Raymond Stevens, The Bridge Institute, University of Southern California
Nuclear magnetic resonance (NMR) spectroscopy complements other structural biology techniques, such as x-ray diffraction, by identifying multiple simultaneously populated conformations in equilibrium. Here, we leverage this advantage to study two human GPCRs. First, we report how a GPCR fusion strategy used for x-ray crystallography influences the protein conformational equilibrium and highlight potential cases where drug-ligand interactions can be affected. Second, we report a novel approach to incorporation of stable isotopic NMR labels into a wild type human GPCR and new insights obtained from this method.
10:50 Next Generation Bio-Sensing: New Opportunities for Challenging Targets
Tim Kaminski, Ph.D., Postdoctoral Fellow, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg
Single molecule experiments enable us, next to its unmatched sensitivity, to directly gain a mechanistic insight into biological processes by observing its stochastic behavior. We are developing a toolbox which advances single molecule microscopy from a method primarily used in academia into a versatile tool for drug discovery. By using this method, we are able to address shortcomings of established biophysical methods as e.g. tight binding limit, working with membrane proteins, higher throughput. Additionally, we are able to extract kinetic profiling of inhibition reactions in solution by observing the association and dissociation of thousands of molecules in parallel with a surface-based single molecule platform.
11:20 Enjoy Lunch on Your Own
12:35 pm Plenary Keynote Program
(click here for details)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing
2:45 Close of Conference
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