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.
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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
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
The commonly used medication for controlling asthma includes bronchodilators and anti-inflammation drugs. Almost all bronchodilators are the agonists of beta2 adrenergic receptor (beta2AR). We report a crystal structure of human beta2AR bound to the
most widely used asthma drug salmeterol, which reveals the bitopic nature of salmeterol and an additional ligand binding site in the receptor. The results provide a structural explanation for the prominent pharmacological characteristics of salmeterol
including high receptor-subtype selectivity and long-lasting action. We also present the first crystal structures of a lipid GPCR, the CRTH2, as a new target for developing small molecule anti-inflammation drugs for asthma. The structures reveal
critical features for the binding of CRTH2 antagonists including a Phase III drug candidate, fevipiprant. They also suggest a novel mechanism for the recognition of endogenous lipid mediators by GPCRs. Based on the structures, we have identified
compounds with novel structural scaffolds as potential antagonists of CRTH2, and propose new strategies for further drug development.
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 Presentation to be Announced
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
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
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Friday, September 28
7:00 am Registration Open
7:30 Interactive Breakfast Breakout Discussion Groups - View Details
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.
New Ways to Screen GPCRs
Moderator: Dean G. Brown, PhD, Director of External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca
- Fragment-based approaches
- Using DNA-encoded library technology
- Understanding signaling bias
Opioid Receptor Targeting
Moderator: Gavril Pasternak, MD, PhD, Chair and Professor of Neurology, Neuroscience, Pharmacology and Psychiatry, Weill Cornell Medical College
- 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?
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 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 Deorphanization: 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 Mechanisms of Biased Agonist Activation of the Angiotensin Receptor
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
10:45 FEATURED PRESENTATION: Receptor Kinetics for Probing Allosteric Modulation and Biased Signaling
Terry 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
Dong Guo, PhD, Jiangsu Key Laboratory of New Drug Research and Clinical
Pharmacy, Xuzhou Medical University, China
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
1:55 Chairperson’s Remarks
Brian J. Murphy, PhD, Senior Principal Scientist, 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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