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CONFERENCE SHORT COURSE*
November 1, 2010
Course 1 12:00 pm – 3:00 pm
Allosteric Modulators of GPCRs
Topics to be Covered
- Introduction to theory, types and kinetics of allosteric modulators
- Screening and assays for small molecule allosteric modulators of GPCRs
- Examples of non-small molecule allosteric modulators of GPCRs
- Case study of discovery and development of a GPCR allosteric modulator with a focus on optimization challenges
- Q&A panel session with the instructors
Course Instructors:
Scott Kuduk, Ph.D., Senior Research Fellow, Medicinal Chemistry, Merck & Co.
Craig Lindsley, Ph.D., Professor, Pharmacology and Chemistry, Vanderbilt University
Y. Gopi Shanker, Ph.D., Senior Scientist, Neuroscience, Amgen
*Separate registration required.
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7:00 am Conference Registration and Morning Coffee
8:30 Chairperson’s Opening Remarks
8:40 Discovery of Ligands for the Hydroxy-Carboxylate Receptors GPR109a and GPR109b
Graeme Semple, Ph.D., Vice President, Discovery Chemistry, Arena Pharmaceuticals
In humans niacin can favourably modulate essentially all serum lipid and lipoprotein parameters. The discovery of putative GPCR molecular targets for niacin (GPR109a and GPR109b) engendered a resurgence of interest in this area that has focused on niacin’s ability to increase HDL-cholesterol as well as the accompanying uncomfortable cutaneous flushing response. In this presentation the identification of agonist ligands for GPR109a and GPR109b via screening and classical SAR approaches will be described. The characterization of distinct signaling pathways within cells of interest led to hypotheses that enabled the identification of two clinical candidates for these receptors which will be described.
9:10 Identification and Characterization of Allosteric Modulators of mGluR4 for the Treatment of Parkinson’s Disease
Y. Gopi Shanker, Ph.D., Senior Scientist, Neuroscience, Amgen
Activation of metabotropic glutamate receptor subtype 4 (mGluR4) has been proposed as a therapeutic strategy for alleviating symptoms of Parkinson’s Disease (PD) and protect against PD-related neurodegeneration by modulating the striatopallidal synapse and restoring balance in the basal ganglia motor circuit. Lack of selective and efficacious mGluR4 agonists has directed efforts at developing positive allosteric modulators (PAMs) which may have a greater potential for subtype selectivity. In this presentation the identification of a potent and selective PAM of mGluR4 as well as its characterization in cell-based assays and pre-clinical animal models will be described.
9:40 Drug Discovery of GPCR (SIP1 or IP)-Targeted Candidate (preliminary title)
John Gatfield, Ph.D., Senior Laboratory Head, Cardiovascular and Fibrosis Biology, Actelion Pharmaceuticals, Ltd.
10:10 Grand Opening Coffee Break in the Exhibit Hall
10:40 Employing Homogenous Time-Resolved FRET to Probe the Quaternary Organization of GPCRs
Graeme Milligan, Ph.D., Professor, University of Glasgow
Time-resolved FRET has become a mainstay of efforts to identity GPCR dimers at the surface of living cells. The adaptation of SNAP- and CLIP- labelling technologies has allowed such studies to be performed without resort to anti-GPCR or anti-epitope tag antibodies. I will illustrate the use of this approach to explore the presence of both cell surface homomers and heteromers and how these may be regulated upon ligand binding.
Sponsored by
11:10 To be Announced
Alan Katz, Ph.D., Chief Scientific Officer, Hudson Robotics
11:25 Sponsored Presentation (Opportunity Available)
11:40 Pathway-Specific Signaling by an Allosteric Modulator
Alice Chen, Ph.D., Group Leader, Drug Discovery, Novartis Research Foundation
Lipid molecule lysophosphatidylcholine (LPC) was initially shown to be the ligand of G2A but that finding was later retracted. We found that LPC appears to be an allosteric modulator that diffirentially affects agonist-induced siganling pathways. It enhanced ERK signaling pathway but inhibited beta-arrestin recruitment and receptor internalization.
12:10 pm Mechanism of Allosteric Modulation by CXCR4 Pepducins
Stephen Hunt III, Ph.D., Senior Vice President, Discovery Research, Anchor Therapeutics
12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on your Own
2:20 Chairperson’s Remarks
2:25 Case Study of GPCR-Based Drug Discovery Using High Content Screening
Frederick Monsma, Ph.D., Director, Kenilworth New Lead Discovery, Merck Research Laboratories
2:55 Intrinsic Reporters of Cell Signaling: High Content Drug Profiling and Characterization of Functional Heterodimers
Stuart Sealfon, Ph.D., Professor and Chair, Neurology, Mount Sinai School of Medicine
The effects of drugs on the state of the cell, organ and organism result from regulation of complex molecular networks. Conventional signaling approaches that capture only one dimension of this network may fail to explain and predict important clinical differences in the effects of pharmacologically similar chemicals. The effects of drugs are not merely determined by their molecular target and their efficacy as agonists or inverse agonists. Examples from diverse fields suggest the importance of conformational selectivity, network topology and context in dictating drug specificity. The development of an approach to high content drug evaluation bridging pharmacology and systems biology that led to the identification of a functional GPCR heterodimer will be presented
3:25 Networking Refreshment Break in the Exhibit Hall
4:05 Optimized 7TMR Assays Forgoing Stable Cell Lines
Robert S. Ames, Ph.D., Director, Cellular Targets/Biological Reagents and Assay Development, GlaxoSmithKline
7TM receptor cell-based drug discovery assays have typically been configured using stable cell lines expressing recombinant receptors. However, there is a long lag time required for stable cell line generation and we have found that reliance on stable recombinant cell lines affords little experimental flexibility. In contrast, transient gene expression using BacMam recombinant modified baculoviruses, can be exploited to facilitate rapid, robust and reproducible cell-based assays. Highlights of how BacMam has been used to transform approaches to cell-based 7TMR high-throughput and SAR drug discovery assays will be presented.
4:35 Using Thermostabilised Receptors (StaRs) to Generate Therapeutic Antibodies to GPCRs
Catherine Hutchings, Ph.D., Antibody Project Leader, Heptares Therapeutics, Ltd.
5:05 Interactive Breakout Discussion Groups
6:15 – 7:15 Happy Hour in the Exhibit Hall
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