Archived Content

GPCR Based Drug Discovery

 

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MONDAY, OCTOBER 1

7:00 am Conference Registration and Morning Coffee


New Structural Insights

8:30 Chairperson's Opening Remarks

Neil Burford, Senior Research Investigator II, Lead Discovery & Profiling, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company
 


8:40 FEATURED PRESENTATION

Crystal Structure of a Lipid G Protein-Coupled Receptor

Michael HansonMichael Hanson, Ph.D., Director, Structural Biology, Receptos

The field of GPCR structural biology has seen a rapid increase of new structural information over the last five years. The techniques used to generate this wealth of data will be examined as will some highlights and milestones achieved along the way. Finally, the utility of GPCR structure determination in the drug discovery process will be assessed.


9:10 Nanobodies for the Structural Analysis of GPCR Transmembrane Signaling

Jan Steyaert, Ph.D., Professor, Structural Biology Department, Vrije University of Brussels

Nanobodies are small (15 kDa) and stable single domain fragments harboring the full antigen-binding capacity of the original heavy chain only antibodies that naturally occur in Camelids. Because of their unique three-dimensional structure, nanobodies have access to cavities or clefts on the surface of proteins. We identified nanobodies that stabilize the b2AR•Gs complex. One of these nanobodies was used to obtain the high resolution crystal structure of this complex, providing the first view of transmembrane signaling.

9:40 How Drugs Bind and Control Their Targets: Characterizing GPCR Signaling through Long-Timescale Simulation

Ron Dror, Ph.D., Senior Research Scientist, D. E. Shaw Research

We report on GPCR-related results from our special-purpose machine that accelerates molecular dynamics simulations of biomolecular systems. Unbiased simulations in which drugs spontaneously associate with GPCRs to achieve bound conformations that match crystal structures almost perfectly are now possible (Nature 482:552-6, 2012). Simulations have also captured transitions of the β2-adrenergic receptor between its active and inactive states, allowing us to characterize the mechanism of receptor activation.

10:10 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing


Screening Strategies


10:40 Session and Panel Introductory Remarks: Probes and Assays for GPCRs

Neil Burford, Senior Research Investigator II, Lead Discovery & Profiling, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company
 


10:55 Biased Signaling and the use of High Content Assays

Andrea Weston, Ph.D., Senior Research Investigator II, Cellular Systems Group, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company

As the inherent complexity of GPCR biology continues to unfold, and the opportunities afforded by exploiting phenomena such as biased agonism and allosteric modulation become more apparent, we have found increasing value to leveraging high-content imaging assays to characterize GPCR ligands. The use of high-content screening to enhance GPCR drug discovery efforts at BMS will be discussed, with focus on the detection and characterization of ligand bias and the study of GPCR internalization and trafficking kinetics.
 

Aurora Spectral Technologies  

11:25 Optical Micro-Spectroscopy Instrumentation and its Application to the Determination of the Quaternary Structure and Distribution in Living Cells of GPCR Homo-Oligomers

Valerica Raicu, Ph.D., Associate Professor, Physics, University of Milwaukee Wisconsin 

This presentation will introduce a novel micro-spectroscopic technique for FRET-based determination of the quaternary structure and localization in living cells of membrane protein complexes and will review results obtained from our recent studies of several G protein-coupled receptors (GPCRs) in living cells.

11:40 Screening Case Studies Using Label Free Approaches

Hong Xin, Ph.D., Scientist/Technologist, Lead Generation, Johnson & Johnson PRD


12:10 TECHNOLOGY PANEL: Tools and Assays for Probing GPCRs

Moderator: Neil Burford, Senior Research Investigator II, Lead Discovery & Profiling, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company

  • Does ligand-biased signaling change the way we screen for GPCR ligands?
  • What are the benefits and challenges of native cell screening?
  • What are the challenges with validating cell-lines/assays for orphan receptor screening?
  • Do hetero-oligomeric receptors represent novel targets for GPCR screening?
 

DiscoverRx12:40pm LUNCHEON PRESENTATION
Investigating Receptor Biology Using PathHunter® Technology: Application to GPCR Trafficking and Internalization

Liz Quinn, Ph.D., Marketing Director, LeadHunter Discovery Services, DiscoveRxThe PathHunter system has been employed to monitor protein interactions and translocation in a cell-based, HTS-friendly format. This technology enables the generation of cellular assays for intractable targets and simplifies detection of cellular signaling events using a simple, one-step chemiluminescent protocol. We previously commercialized >220 GPCR targets that monitor receptor activity through Arrestin recruitment. Here, we discuss the application of the technology to receptor trafficking in response to pharmacochaperone activity and receptor internalization in response to agonist activation.


GPCR-Targeted Drug Candidates

2:20 Chairperson's Remarks

2:25 Discovery of an Orally Available Prostacyclin (PGI2) Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension

Graeme Semple, Ph.D., Vice President, Discovery Chemistry, Arena Pharmaceuticals, Inc.

The design and optimization of new prostacyclin receptor agonists with oral activity in rat models of pulmonary arterial hypertension will be described. As well as in vitro and in vivo potency, special attention was paid to pharmacokinetic parameters eventually resulting in the discovery of the clinical candidate, APD811.

2:55 Case Study in Quantifying Potency and Mode of Action of a Small Molecule Antagonist of a Class B Receptor, CRF1

Simeon RamseySimeon Ramsey, Ph.D., Senior Principal Scientist, Inflammation, Pfizer

This presentation will highlight the utility of a non-equilibrium receptor-ligand binding assay to quantify the binding kinetics of small molecule antagonists to the CRF1 receptor and how data from this platform was used to explain apparent non-competitive, insurmountable antagonism observed in cell based functional assays. It also demonstrates how these kinetic data can be used to design, interpret and predict in vivo receptor occupancy.
 

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing

4:05 Orexin Receptors and the Physiology/Pharmacology of Sleep

Timothy Lovenberg, Ph.D., Senior Research Fellow, Neuroscience, J&J La Jolla

This talk will cover the distinct roles of Orexin-1 and Orexin-2 receptors in the sleep-inducing effects of Orexin receptor antagonists.

4:35 Targeting Novel Regulatory Mechanisms of PDE4 as Potential New Treatments for Mood Disorders

James A. Bibb, Ph.D., Associate Professor, Departments of Psychiatry, and Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center

A new regulatory mechanism by which PDE4 is activated in brain will be presented as a novel target for therapy development. We will demonstrate the antidepressant effects of disrupting this mechanism using small interfering peptides in animal paradigms modeling depression. This may be the first demonstration that it is sufficient to target cAMP/PKA activity in the nucleus accumbens to achieve antidepressant-like effects. Our results underscore the potential of selectively targeting intracellular signaling mechanisms for drug development.


5:05 Interactive Breakout Discussion Groups

Sharing Orphan Receptor Strategies

Moderator: Neil Burford, Senior Research Investigator II, Lead Discovery & Profiling, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company

  • Current approaches
  • Examples
  • Does my ligand bind allosterically?

Exploiting Ligand-Biased Signaling

Moderator: Patricia McDonald, Ph.D., Associate Scientific Director, Translational Research Institute, Scripps Florida

  • Therapeutic benefits and examples
  • Screening strategies to identify ligand bias
  • Quantifying Ligand Bias
     

Using GPCR Structural Data for Drug Discovery

Jan Steyaert, Ph.D., Professor, Structural Biology Department, Vrije University of Brussels


6:15 – 7:30 Welcoming Reception in the Exhibit Hall with Poster Viewing



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2014 Discovery on Target Brochure  

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PREMIER SPONSOR 

Cellecta 

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SPONSORSHIPS & EXHIBITS 

The exhibit hall was sold out in 2013, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2014, contact:

Jon Stroup
Business Development Manager
781-972-5483
jstroup@healthtech.com 

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CONFERENCES


October 8 – 9

Targeting Epigenetic Readers and
Chromatin Remodelers
 

Targeting the Ubiquitin Proteasome System  

Big Data Analytics and Solutions  

GPCR-Based Drug Discovery  

RNAi for Functional Genomics Screening
– Part 1
 

Protein-Protein Interactions as Drug Targets  

Antibodies Against Membrane Protein Targets
– Part 1
 


October 9 – 10

Targeting Histone Methyltransferases and Demethylases  

Screening Drug Transporter Proteins  

Maximizing Efficiency in Discovery  

GPCR-Targeted Therapeutics  

Genome Editing for Functional Genomics
Screens – Part 2
 

Cancer Metabolism  

Antibodies Against Membrane Protein Targets
– Part 2
 


SYMPOSIUM


October 7

Next Generation Histone Deacetylase Inhibitors  


SHORT COURSES


October 7

SC1: Designing Scalable Software Systems for Big Data Analytics  

SC2: Approaches for Biologically-Relevant Chemical Diversity  

SC3: Setting Up Effective RNAi Screens: From Design to Data to Validation  

SC4: Targeting Protein-Protein Interactions  

SC5: GPCR Structure-Based Drug Discovery  

SC6: Advances in Metagenomic Drug Discovery for New Anti-Infective Agents  

SC7: Targeting of GPCRs with Monoclonal Antibodies  

SC8: A Primer to Gene Editing: Tools and Applications  

SC9: Introduction to Targeted Covalent Inhibitors  


October 9

SC10: Setting Up Effective Functional Screens Using 3D Cell Cultures  

SC11: Integration of BDDCS and Extended Clearance Principles  

SC12: Introduction to Allosteric Modulators and Biased Ligands of GPCRs  

SC13: Introduction to Drug Metabolism