Cambridge Healthtech Institute's 2nd Annual

GPCR-Targeted Drug Design

New Structural, Pharmacological and Biophysical Insights and Tools

April 3-4, 2018 | Hilton Bayfront | San Diego, California


G protein-coupled receptors (GPCRs) represent a highly medically relevant class of proteins because of the central role they play in a range of physiologically critical processes from vision to heart and breathing functions to CNS processes. This meeting will focus on discovery and development of small molecules with drug potential that target GPCRs. Many of the medicines on the market today act on only a small percentage of the GPCRs in our body and were discovered over a decade ago without knowledge of the specific receptor(s) they target. That information coupled with the explosion of X-ray crystal structures now available for all classes of GPCRs as well as new biophysical techniques to study the more intractable ones, has renewed interest within the pharmaceutical industry in discovering new medicines that target GPCRs. This conference convenes leading researchers from industry as well as academics to share insights on GPCR structure and function. Discuss with fellow medicinal chemists, structural biologists, pharmacologists and translational researchers, the impact of new GPCR knowledge and tools in today's target-focused era of drug discovery.

Final Agenda

Tuesday, April 3

7:00 am Registration and Morning Coffee


8:00 Welcome Remarks

Anjani Shah, PhD, Conference Director,Cambridge Healthtech Institute

8:05 Chairperson's Opening Remarks

Andrew Alt, PhD, Associate Director, Biology, Arvinas

8:10 FEATURED PRESENTATION: β-arrestin Desensitization Cycles and Biosensor Assays

Martin Lohse, PhD, Chairman, Max Delbruck Center, Berlin, Germany

Optical analyses are providing new aspects in the analysis of GPCRs. Most notably, their activation and signaling can be monitored in real time and in intact cells by FRET microscopy. Motility and interactions can be studied by single molecule microscopy. These methods can also be used to investigate downstream signaling and to discover bias in G-protein- vs. beta-arrestin-mediated signals. They have allowed the discovery of multiple active states of beta-arrestins, suggesting that beta-arrestins undergo an activation/deactivation cycle. Differential effects of various ligands indicate that they may differ in their physiological effects by selectively stimulating distinct kinase pathways.

9:10 Sponsored Presentation (Opportunity Available)

9:40 Coffee Break

10:05 GPCR-Targeted Lead Optimization: The Importance of the Assay in Fitting Data to Models

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.

10:35 A New Tool for GPCR Thermo-Stabilization

Seva Katritch, PhD, Assistant Professor, The Bridge Institute, University of Southern California

11:05 GPCR Allosteric Coupling Investigated by NMR and X-Ray Diffraction

Matthew Eddy, PhD, Postdoctoral Fellow, Laboratory of Raymond Stevens, University of Southern California and The Scripps Research Institute

Drug binding in human GPCRs is allosterically connected over 30 A to the intracellular signaling surface. Using advanced techniques for stable isotope labeling, we probe this allosteric network with NMR spectroscopy in solution for a native GPCR and variant with strikingly different signaling properties. X-ray crystal structures of the same variant reveal local conformational rearrangements in a known signaling-related structural motif. In parallel, NMR data uncover large signaling-related changes in conformational dynamics. Information from both techniques paired together provides a comprehensive picture of changes in structure and dynamics underpinning GPCR allosteric coupling.

11:35 Luncheon Presentation: Reaching beyond Developing Stable GPCR Cell Lines

Lisa Minor, Scientific Consultant, Multispan, Inc.

Developing high quality assays is paramount for drug discovery screening. Multispan devoted significant effort in developing signaling and phenotypic assays using endogenous targets such as RXFP1 in THP-1, CGRP in SK-N-MC, AMPK in C2C12, and DNA-PK in HELA cells. We also developed stable cell line assays for CGRP, AM, and Amylin by studying and overcoming endogenous RAMP expression and designed a 32-GPCR panel comprising CNS and cardiovascular liability targets. In addition to radioligand binding, we established a FACS-based quantification of GPCR expression to benchmark target expression against physiological level in native cells.

12:20 pm Session Break


1:15 Chairperson's Remarks

JoAnn Trejo, PhD, MBA, Professor and Vice Chair, Department of Pharmacology, Associate Dean for Health Sciences Faculty Affairs, University of California, San Diego

1:20 GPCRs as Targets in Cancer

Paul A. Insel, MD, Distinguished Professor, Pharmacology and Medicine; Co-Director, Medical Scientist MD/PhD Training Program, University of California, San Diego

Emerging data suggest that GPCRs contribute to malignancy and certain GPCRs have higher expression in tumors compared to normal tissue. Using multiple approaches to assess GPCRs in human tumors, cancer cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment, we find that tumors, cancer cells and CAFs have higher expression of many GPCRs. Confirmatory, validation data exist for multiple such GPCRs in pancreatic cancer, a highly lethal cancer in need of new, effective therapies.

1:50 Illuminating the Onco-GPCRome

J. Silvio Gutkind, PhD, Professor, Department of Pharmacology; Associate Director of Basic Science, Moores Cancer Center, UCSD

Recent large cancer sequencing initiatives have revealed that more than 25% of all human malignancies harbor mutations in G proteins and GPCRs, and that certain GPCR families are aberrantly expressed in multiple human neoplasia. We will present new evidence supporting the potential clinical benefit of targeting GPCRs, G proteins, and their regulated signaling circuitry for cancer prevention and treatment. How GPCRs modulation can be exploited to increase the response to new immunotherapies will be discussed.

2:20 Anti-Leukemic Activity of Imipridone ONC212 via Selective Targeting of Orphan GPCR GPR132/G2A

Varun Vijay Prabhu, PhD, Associate Director, Research and Development, Oncoceutics, Inc.

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 using the PathHunter® β-Arrestin assay (DiscoverX) and multidose validation revealed that imipridone ONC212 selectively targets orphan GPCR GPR132/G2A at nanomolar concentrations. BIOSENS-ALL BRET assay (Domain) showed that ONC212 promotes Gq family activation downstream of GPR132. ONC212 was non-toxic to normal cells at therapeutic concentrations and demonstrated robust in vivo safety/efficacy in leukemia xenograft models.

2:50 Therapeutic Promise of Allosteric Modulators of Angiotensin II Receptor

Sadashiva Karnik, PhD, Professor, Molecular Cardiology, Lerner Research Institute, Cleveland Clinic

Novel allosteric modulators were discovered based on crystal structure and computer assisted drug development. These novel molecules showed high specificity and efficacy in pharmacological and signaling studies. In vivo evaluation in animal models are in progress. This will be the first report of allosteric chemotypes for any angiotensin receptor.

3:20 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

4:35 Plenary Keynote Introduction

Kevin Lustig, PhD, CEO,

4:40 PLENARY KEYNOTE: Targeting Ras and MYC for the Treatment of Cancer

Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine

Two of the most important targets in cancer are Ras and MYC. However, both of these highly validated cancer targets are thought to be undruggable. In this presentation, I will discuss our approaches for targeting both of these proteins directly and indirectly using fragment-based methods and structure-based design.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:30 End of Day

Wednesday, April 4

7:30 am Continental Breakfast Breakout Discussions


8:30 Chairperson's Remarks

Irina Kufareva, PhD, Project Scientist, Handel and Abagyan Lab, The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

8:35 Ubiquitin-Mediated Inflammatory Signaling by GPCRs

JoAnn Trejo, PhD, MBA, Professor and Vice Chair, Department of Pharmacology, Associate Dean for Health Sciences Faculty Affairs, University of California, San Diego

Ubiquitination of 40 mammalian GPCRs has been reported, but despite the rich complexity of GPCR signaling, ubiquitination is attributed largely to GPCR degradation. We discovered that ubiquitination of GPCRs promotes p38 activation on endosomes via recruitment of TAB2, which co-associates with TAB1 that directly binds to p38a. TAB1-dependent p38 activation is critical for PAR1-mediated endothelial inflammatory responses. The mechanisms by which GPCR-induced p38 endosomal inflammatory signaling is regulated is not known and will be discussed.

9:05 Exploration of Endosomal GPCR Signaling Using Electron Microscopy

Alex Thomsen, PhD, Postdoctoral Fellow, Lefkowitz Lab, Department of Medicine, Duke University

We recently demonstrated that a class of GPCRs promote 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 (cryo-electron tomography, cryo-ET).

9:35 Coffee Break in the Exhibit Hall with Poster Viewing


10:30 Discovery of Small Molecule Protease-Activated Receptor 2 (PAR2) Antagonists

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.

11:00 Drug-Target Binding Kinetics - A Case for GPCRs

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

It is now emerging that determining drug target binding kinetics, next to traditional potency measures, may improve the success rate of a candidate drug moving through the clinical development. 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.

11:30 Kinetic Drug Discovery for GPCRs

Sam Hoare, PhD, Founder and Chief Scientist, Pharmacology Data Analysis, Pharmechanics, LLC

Novel paradigms are needed for translating the raw data emerging from new molecular biosensor and reader technology-based assays into meaningful pharmacological activity parameters that can be used for structure-activity analysis. We have developed a new kinetic data analysis framework that, using standard curve-fitting software, yields values of the rate of onset of the response, and the total signal produced. Here we will show the resulting structure-activity kinetics for beta2 adrenoceptor signaling, and for biased agonism at the D2 dopamine receptor.

12:00 pm End of Conference

* The program is subject to change without notice, due to unforeseen reason.