2016 Archived Content

GPCR-Based Drug Discovery - Part 2 Header

G protein-coupled receptors (GPCRs) have steadily remained an important target class for drug discovery because of the myriad of biological processes they initiate as transducers of extracellular signals to inside the cell. The second meeting of our two-part set, Part 2: Signaling and Pharmacological Complexities, explores the unique aspects of GPCR signaling which makes the receptors such challenging yet fruitful targets. With the difficulties of targeting GPCRs also come multiple avenues for their pharmacological modulation. Insights on receptor trafficking, modifications, desensitization and selective/biased coupling and how that impacts design of GPCR-targeted compounds will be discussed. Case studies of GPCR-targeted compounds advancing in preclinical or clinical development, including biased ligands and allosteric modulators, will also be featured. 

Final Agenda


• September 19 Short Course: GPCR Structure-Based Drug Discovery

• September 20-21 Conference: GPCR-Based Drug Discovery - Part 1

• September 21-22 Conference: GPCR-Based Drug Discovery - Part 2

• September 21 Short Course: Introduction to Allosteric Modulators

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Wednesday, September 21

11:20 am Conference Registration Open

11:25 Enjoy Lunch on Your Own

2:40 Refreshment Break in the Exhibit Hall with Poster Viewing

GPCR Complexities: Allosterism, Biased Signaling and More

3:20 Chairperson’s Opening Remarks

Annette Gilchrist, Ph.D., Professor, Pharmacology, Midwestern University

3:35 Directing Opioid Receptor Signaling to Improve Analgesic Therapies

Laura M. Bohn, Ph.D., Professor, Departments of Molecular Therapeutics & Neuroscience, The Scripps Research Institute

GPCRs propagate signals via interactions with multiple effectors, including G proteins and {beta}arrestins. GPCRs in different contexts, such as different neuronal populations or different cellular compartments, can couple to different effectors. We are finding that opioid receptor ligands that promote signaling towards G protein signaling over {beta}arrestin recruitment in vitro can be used to dissociate from analgesic responses and certain side effects in vivo.

4:05 GPCR-Mediated G Protein Activation

Heidi Hamm, Ph.D., Professor, Department of Pharmacology, Vanderbilt University Medical Center

GPCR mediated heterotrimeric G protein activation is an obligate step in signal transduction. Our laboratory has used biophysical approaches to show that GPCRs open up a binding site during activation that interacts with Gα’s alpha 5 (α5) helix leading to a rigid body rotation and translation of this helix. The repositioned α5 helix changes its hydrophobic interactions with the core of the protein, leading to allosteric changes, nucleotide release and G protein activation.

PerkinElmer NEW 20094:35 360 Degree Characterization of GPCR Function through Ligand Binding, Functional and Phenotypic Analyses

Roger Bosse, Ph.D., Senior Market Segment Leader, PerkinElmer

We will present several examples showing how combining ligand binding, functional and phenotypic analyses, leads to the discovery and development of an entirely new generation of GPCR drugs including allosteric regulators, inverse agonists and drugs targeting hetero-oligomeric complexes.

5:05 Refreshment Break in the Exhibit Hall with Poster Viewing

5:40 Positive Allosteric Modulators of mGlu4 for the Treatment of Parkinson’s Disease: From HTS to Pre-Clinical Leads

Corey R. Hopkins, Ph.D., Associate Professor, Department of Pharmaceutical Sciences, University of Nebraska Medical Center 

Disorders of the CNS remain some of the most elusive targets for the pharmaceutical industry and academic researchers to tackle. Although Parkinson’s disease (PD) is the second most common neurodegenerative disease, no effective long term treatment or cure has been developed. Utilizing a functional HTS and medicinal chemistry approach, we have discovered a novel series of PAMs of the metabotropic glutamate receptor 4 (mGlu4).

6:10 Structural Basis of Allostery in Chemokine Receptors 

Irina Kufareva, Ph.D., Project Scientist, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego  

Interaction of chemokines with 7TM receptors on cell surface drives cell migration in the context of development, immunity, inflammation, and cancer, making it an attractive therapeutic target. However, therapeutic development has been hindered by the pharmacological complexities of receptor:chemokine system and by the inherently limited druggability of receptor:chemokine interfaces. Allosteric regulators may be a new word in the discovery of anti-chemokine receptor therapeutics. Using molecular modeling, biophysical and functional experiments, and X-ray crystallography, we obtained first insights into the structural basis of allostery in CXCR4, CCR2, and CCR5. 

6:40 End of Day

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Thursday, September 22

7:30 am Registration Open and Morning Coffee


8:30 Chairperson’s Remarks

Jeffrey L. Benovic, Ph.D., Professor and Chair, Department of Biochemistry & Molecular Biology, Thomas Jefferson University

8:45 FEATURED PRESENTATION: GPCRs in Cancer: An Untapped Opportunity

Paul Insel, M.D., Distinguished Professor, Pharmacology and Medicine, University of California San Diego

GPCRs are the most common drug targets but have largely been ignored as therapeutic targets in cancer, other than endocrine-driven tumors, even though GPCRs can regulate many features of the malignant phenotype. Thus, GPCRs may be useful targets directed at cancer cells themselves but in addition, in cells of the tumor microenvironment—including in pancreatic cancer, a tumor in desperate need of new therapies.

9:15 Desensitization of Cardiac Adrenergic Receptor Signaling through Receptor Cross-Talk

Kevin Xiang, Ph.D., Professor, Pharmacology, University of California Davis

A growing list of cell receptors, including GPCRs, RTKs, and cytokine receptors, impair cardiac adrenergic receptor via both GRKs and second messenger-dependent kinases. Here, I will focus on the impacts of hyperinsulinemia on development of cardiac dysfunction associated with Type-2 diabetes and obesity, and discuss the phosphodiesterase 4D in the cross talk between insulin receptor and adrenergic receptor in heart.

9:45 Selected Poster Presentations

10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

11:10 Discovery of the First Orally Bioavailable GPR39 Agonists

Vidya Kunjathoor, Ph.D., Scientist, Cardiovascular & Metabolic Disease Area, Novartis Institutes for BioMedical Research, Inc.

We report on the identification of highly potent and orally bioavailable GPR39 agonists in mice. The compound was found in a phenotypic screening campaign and was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes.

11:40 CXCR4 Cyclic Peptide Antagonists for Cancer

Sheng Bin Peng, Ph.D., Group Leader and Senior Research Advisor, Eli Lilly & Co.

We present on our anti-CXCR4 cyclic peptide inhibitor that is now in Phase 2 clinical studies for human hematological malignancies.

12:10 pm Lunch on Your Own

1:30 Refreshment Break in the Exhibit Hall with Poster Viewing


2:15 Chairperson’s Remarks

Irina Kufareva, Ph.D., Project Scientist, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

2:20 FEATURED PRESENTATION: Arrestin/Rhodopsin Crystal Structure and Implications for Drug Design

H. Eric Xu, Ph.D.,Professor, Cancer Research, Van Andel Institute (VAI)

I present the work of our team on using SLAC’s Linac Coherent Light Source (LCLS), the world’s first hard X-ray free electron laser, to generate the first three-dimensional map of arrestin while it was linked with a GPCR. This capability allowed us to create a three-dimensional image of the arrestin-rhodopsin complex at an atomic level—a much higher resolution than is possible with conventional X-ray technology.

2:50 Biasing Beta2-Adrenergic Receptor Signaling

Jeffrey L. Benovic, Ph.D., Professor and Chair, Department of Biochemistry & Molecular Biology, Thomas Jefferson University

GPCRs interact with three families of proteins in a ligand-dependent manner: G proteins, GRKs and arrestins. These interactions play an essential role in regulating GPCR signaling, trafficking and degradation. I will discuss recent strategies that we have used to bias b2-adrenergic receptor signaling to promote Gs bias to regulate airway function and arrestin bias to regulate cardiovascular function.

3:20 Session Break

3:30 Late Breaking Presentation: SCFA Receptors are Novel Mediators of Pancreatic β Cell Function

Brian Layden, M.D., Ph.D., Associate Professor, Department of Medicine, University of Illinois at Chicago

Nutrient sensing receptors are key metabolic mediators. Two nutrient sensing receptors, short chain fatty acid (SCFA) receptors (FFA2 and FFA3) are uniquely responsive to gut microbiota derived nutrients (such as acetate, propionate, and butyrate). Recent studies have investigated their role in pancreatic β cell biology. Through a combination of studies, we have helped define their role in β cell function, revealing new therapeutic opportunities for type 2 diabetes.

4:00 Targeting G Protein β/γ Subunit Signaling

Alan V. Smrcka, Ph.D., Professor, Pharmacology and Physiology, University of Rochester School of Medicine

Our laboratory has identified a number of small molecules that inhibit various aspects of G β/γ subunit function. This presentation will discuss the biochemical basis for the mechanism of action of these compounds, their pharmacological efficacy in various preclinical models of disease, and their utility in the dissection of GPCR signaling pathways.

4:30 Extended cAMP GPCR-Generated Signaling

Thomas J. Gardella, Ph.D., Associate Professor, Medicine, Massachusetts General Hospital, Harvard

5:00 Close of Conference

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