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GPCR-Based Drug Discovery

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November 1, 2010

Course 1   12:00 pm – 3:00 pm

(lunch provided courtesy of Anchor Therapeutics)


Allosteric Modulators of GPCRs 

12-12:45pm Allosteric Modulators: Introduction

Shaun R. Stauffer, Ph.D., Research Assistant Professor of Pharmacology, Director of Medicinal Chemistry, Vanderbilt Program in Drug Discovery, Co-Director Vanderbilt Specialized Chemistry Center, Vanderbilt University Medical Center

  • Theory, types and kinetics of allosteric modulators
  • Advantages of allosteric modulators
  • Examples of non-small molecule allosteric modulators of GPCRs (and other receptors) -- what's currently on the market and how they were discovered and brief mention of those known to be in development

1:00-1:30pm Screening approaches for disovering allosteric modulators

Annette Gilchrist, Ph.D., Assistant Professor, Midwestern University, Chicago College of Pharmacy

  • Pros and cons of various common screening and hit-to-lead approaches
  • Suggested solutions for screening pitfalls

1:30-1:45pm -- Coffee Break

1:45-2:15 - Case study of discovery and development of a GPCR allosteric modulator

Scott Kuduk, Ph.D., Senior Research Fellow, Medicinal Chemistry, Merck & Co.

  • Focus will be on optimization challenges

2:15-3pm Q&A panel session with instructors

Annette Gilchrist, Ph.D., Assistant Professor, Midwestern University, Chicago College of Pharmacy

Frederick Jones, M.D., President and Chief Executive Officer, Anchor Therapeutics

Scott Kuduk, Ph.D., Senior Research Fellow, Medicinal Chemistry, Merck & Co.

Shaun R. Stauffer, Ph.D., Research Assistant Professor of Pharmacology, Vanderbilt University Medical Center

*Separate registration required.

Lunch provided courtesy of Anchor Therapeutics


7:00 am Conference Registration and Morning Coffee


GPCR’s In Disease

8:30 Chairperson’s Opening Remarks

Thue Schwartz, Ph.D., Professor, The Novo-Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen


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 Comparative evaluation of Allosteric Inhibitors for the Chemokine Receptor CCR1

Annette Gilchrist, Ph.D., Assistant Professor, Midwestern University, Chicago College of Pharmacy

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


Probing Signaling Complexities

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
Hudson Robotics 
11:10 Accelerating Lead Optimization of Drug Candidates Through Iterative Screening and Modeling

Alan H. Katz, Ph.D., Chief Scientific Officer, Hudson Robotics, Inc.
We recently developed a novel automated system that integrates a robotic screening workcell with computer-aided drug design (CADD) tools, which run iteratively under the control of proprietary instrument software.  The CADD portion systematically generates models that are consistent with biological activity, which the robots then validate by cherry-picking and screening key samples.  The resulting biological data is directly incorporated from the reader to improve the models.  Each iteration also produces lists of chemical structures that can be purchased or synthesized, as well as known compounds whose activity supports the developing hypotheses.   We will demonstrate how this approach can be used in the discovery of GPCR-targeted drugs.

Sponsored by
11:25 Harnessing the Benefits of GPCR Signaling Complexity with the CellKey® System
Catherine Parrish, Application Scientist, Molecular Devices, Inc.
The past decade has seen a growing understanding that the complexity of GPCR pharmacology is far greater than anticipated, and that assays which examine only single-points in signaling pathways do not address these intricacies.  Gaining a greater understanding of G-protein signal transduction mechanisms and their impact that they can have on data interpretation is key to the future success of GPCR drug discovery. Label-free cell-based assays reflect the integrated whole-cell response to stimulus and provide an important tool in the arsenal of applications available for scientists involved in GPCR drug discovery. During this presentation attendees will be updated on recent work performed with Molecular Devices’ label-free CellKey® System. Topics will include application of the CellKey System for study of complex receptor-associated behaviors, including pleiotropic signaling and functional selectivity.

11:40 Use of Encoded Library Technology for Discovery of Small Molecule Ligands to GPCRs
David Israel, Ph.D., Director of Cell and Molecular Technologies, Molecular Discovery Research Boston, GlaxoSmithKline
Encoded library technology (ELT) is a combinatorial chemistry method for small molecule drug discovery, where billions of small molecules, each attached to a unique DNA sequence that encodes the structure of the molecule, are interrogated for binding to a drug target. ELT selection methods against pure, soluble protein targets have been previously described (Clark et. al. Nature Chemical Biology 5:647-654, 2009). Here, we describe the development, validation, and application of an ELT selection method for integral membrane protein targets and its successful use against several GPCRs.

12:10 pm Mechanism of Allosteric Modulation by CXCR4 Pepducins

Stephen Hunt III, Ph.D., Senior Vice President, Discovery Research, Anchor Therapeutics

Sponsored by
12:40 Luncheon Presentation 
Accelerate Your Research with OriGene's GPCR Resource: cDNA Clones, shRNAs, and Stable Cell Lines
Xuan Liu, Ph.D., Director of Marketing, OriGene
Functional gene study usually involves perterbation of expression levels with cDNA clones for over expresson and shRNA/siRNA for knockdown. OriGene provides comprehensive tools for GPCR functional study, The product includes cDNA clones, shRNA, siRNAs, proteins , antibodies, and stable cell lline development. The session will introduce OriGene's tool box for GPCR research and other gene famiily or pathway study.

New Approaches To GPCR Drug Discovery

2:20 Chairperson’s Remarks

2:25 Case Study of GPCR-Based Drug Discovery Using High Content Screening

Lisa Smith, M.S., Scientist, In Vitro Pharmacology, Merck Research Labs

HIV entry is mediated through CD4 and the chemokine receptors CXCR4 and/or CCR5.  A T-cell tropic HIV cell fusion assay was established using U2OS cells expressing the envelope glycoprotein gp160 from HIV NL4-3 (transduced by BacMam virus) and HeLa cells expressing CD4 and CXCR4.  High content analysis of the cell fusion event is based upon a Gal4/VP16-activated beta-lactamase signal.  Measurement of changes in morphology associated with cell fusion was combined with beta-lactamase activity to show robust assay statistics in 384-well and 1536-well plates.

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

In this interactive session, delegates choose a breakout topic of interest (listed below) and join the moderated discussion at hand. Participants are encouraged to share examples from their work, vet ideas with peers and be part of a group problem-solving endeavor. We emphasize that this discussion is an informal exchange amongst scientists and is not meant to be, in any way, a corporate or product discussion.

Topic: The ‘under-class’ of GPCRs: Class C Receptors

Moderator: To be Announced

  • Structural and pharmacological features of class C receptors
  • Opportunities and challenges for drug discovery
  • Are there unique opportunities to identify allosteric modulators of class C receptors?

Topic: Deploying GPCR Crystal Structures to Screening and Design: Opportunities and Challenges

Moderator: Sidney Topiol, Ph.D., CSO 3D-2Drug and Associate Director, Computational Chemistry, Lundbeck

  • What balance is needed and/or anticipated between X-ray structures and derived
    homology models?
  • How does understanding of complex molecular mechanisms (active/inactive
    state, trafficking, dimerization) affect structure based drug discovery?
  • What are the merits, opportunities and challenges in designing allosteric

Topic: Challenges of Generating Therapeutic Biologics to GPCRs:

Moderator: Catherine Hutchings, Ph.D., Antibody Project Leader, Heptares Therapeutics, Ltd.

Share and learn about successes and failures in targeting GPCR therapeutic targets with non small molecules such as:

  • Peptides
  • Antibody fragments
  • Whole IgG molecules

6:15 – 7:15 Happy Hour in the Exhibit HallSponsored by
Sophion logo

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Final Agenda Now Available









The exhibit hall was sold out in 2015, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2016, contact:

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Sr. Business Development Manager






Next-Generation Histone Deacetylase Inhibitors

Strategies for Tackling Rare Genetic Diseases

Understanding CRISPR: Mechanisms and Applications

Autoimmunity – Small Molecule Approaches

NK Cell-Based Cancer Immunotherapy

Medical Dermatology Therapeutic R&D and Technical Innovation



Targeting Histone Methyltransferases and Demethylases

Targeting the Ubiquitin Proteasome System

Targeting the Microbiome
– Part 1

GPCR-Based Drug Discovery - Part 1

Advances in Gene Editing and Gene Silencing – Part 1

Gene Therapy Breakthroughs

Antibodies Against Membrane Protein Targets – Part 1

Targeting Cardio-Metabolic Diseases

Targeting Ocular Disorders


Targeting Epigenetic Readers and Chromatin Remodelers

Kinase Inhibitor Discovery

Targeting the Microbiome
– Part 2

GPCR-Based Drug Discovery - Part 2

Advances in Gene Editing and Gene Silencing – Part 2

Translating Cancer Genomics

Antibodies Against Membrane Protein Targets – Part 2

Metabolomics in Drug Discovery

TRAINING SEMINAR: Data Visualization


Monday, September 19
8:00 - 11:00 am

(SC1) Immunology Basics for Chemists

(SC2) Designing Peptide Therapeutics for Specific PPIs

(SC3) Phenotypic Screening and Chemical Probe Development

(SC4) Medical Dermatology Therapeutic R&D and Technical Innovation - Part 1

Monday, September 19
2:00 - 3:00 pm

(SC5) GPCR Structure-Based Drug Discovery

(SC6) RNA as a Small Molecule Drug Target

(SC7) Using IP Landscape Studies to Improve Your Confidence

(SC8) Medical Dermatology Therapeutic R&D and Technical Innovation - Part 2

Monday, September 19
3:30 - 6:30 pm

(SC9) Targeting of GPCRs with Monoclonal Antibodies

(SC10) Introduction to Targeted Covalent Inhibitors

(SC11) Contact Lens Drug Delivery Systems

(SC12) Introduction to Gene Editing

Monday, September 19
7:00 - 9:30 pm

(SC13) Convergence of Immunotherapy and Epigenetics for Cancer Treatment

Wednesday, September 21
7:00 - 9:30 pm

(SC14) Cancer Metabolism: Pathways, Targets and Clinical Updates

(SC15) Introduction to Allosteric Modulators and Biased Ligands of GPCRs

(SC16) Functional Screening Strategies Using CRISPR and RNAi

(SC17) Challenges and Opportunities in DNA Methyl Transferase (DNMT) Inhibitors as Therapeutics