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Allosteric modulation has taken off recently in applications to the drug discovery arena, especially where G Protein-Coupled Receptors (GPCRs) are involved. Not only can allosteric modulators be developed as drugs to selectively activate specific functions of a GPCR or other target and thereby reduce the risk of side-effects, but allosteric modulators can also be used as tools in drug discovery to decipher the signaling complexities of a GPCR. At Cambridge Healthtech Institute’s inaugural day and a half meeting devoted to Allosteric Modulators, hear case studies about the discovery and optimization of allosteric modulators for GPCRs and a few non-GPCR targets as well.

THURSDAY, NOVEMBER 3

 

Identifying Allosteric Modulators:
Theory and Screening Approaches

1:30 pm Chairperson’s Remarks

Andrew Alt, Ph.D., Senior Research Investigator, Lead Discovery, Bristol Myers Squibb

1:40 KEYNOTE PRESENTATION:

7TM Receptor Drug Discovery: An Allosteric View of Shapeshifting Proteins

Terrence KenakinTerry P. Kenakin, Ph.D., Professor, Department of Pharmacology, University of North Carolina School of Medicine

As new drug screening increasingly uses functional rather than traditional binding assays, allosteric ligands often enter the drug discovery process through happenstance. However the need for specifically designed allosteric screens is growing. The therapeutic potential of allosteric molecules due to their unique properties of permissive, saturable and probe dependent activity is becoming well recognized.This talk discusses properties of allosteric ligands, how they can be detected and procedures for quantifying their activity for lead optimization.

2:40 A Case Study: Evaluating Allosteric Modulators of CCR1 for Multiple Myeloma

Annette Gilchrist, Ph.D., Assistant Professor, Pharmaceutical Sciences, Midwestern University

Osteolytic bone destruction is one of the most frequent complications of multiple myeloma (MM), a clonal B-cell disorder characterized by the accumulation of malignant plasma cells in the bone marrow. Studies have recently emerged that suggest a role for the chemokine receptor CCR1 in multiple myeloma progression. To evaluate the role of CCR1 in MM we used several previously described allosteric small molecule inhibitors. Results from radioactive binding assays, and beta-arrestin translocation assays will be presented.

3:10 Networking Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Opportunities and Challenges in Developing High-Throughput Screens for Allosteric Modulators of G Protein-Coupled Receptors

Andrew Alt, Ph.D., Senior Research Investigator, Lead Discovery, Bristol Myers Squibb

Allosteric modulation of G protein-coupled receptors is an emerging therapeutic strategy that can potentially provide improved selectivity and safety, along with maintenance of spatial and temporal regulation associated with native receptor signaling. Accordingly, drug discovery efforts at GPCR targets have increasingly focused on the identification of allosteric modulators. This presentation will focus on the special challenges, opportunities and current strategies for high-throughput screening for allosteric GPCR modulators, with particular focus on the identification of positive allosteric modulators.

4:15 Sponsored Presentations (Opportunities Available)

4:45 Positive Allosteric Modulation of Metabotropic Glutamate Receptors in Neurotransmission: Specific Activity-Dependent Regulation of Defined Synaptic Circuits in vivo

Thomas Salt, Ph.D., Professor, Visual Neuroscience, University College London Institute of Ophthalmology

This talk will review use of Positive Allosteric Modulators (PAMs) to enhance mGlu synaptic and extra-synaptic function. I will show how PAMs can affect synaptic function under different physiological and pathological conditions in the whole organism based on recent experimental data on PAM action in thalamic circuitry from various groups (including the presenter’s). This will be placed in the context of how PAMs can affect sensory/pain processes, cognitive processes, schizophrenia, and epileptic mechanisms in vivo.

5:15 Panel Discussion: Screening for Allosteric Modulators

Andrew AltModerator: Andrew Alt, Ph.D., Senior Research Investigator, Lead Discovery, Bristol Myers Squibb




 

Panelists: Terry P. Kenakin, Ph.D., Professor, Department of Pharmacology, University of North Carolina School of Medicine; Scott Kuduk, Ph.D., Senior Research Fellow, Medicinal Chemistry, Merck & Co.; Craig Lindsley, Ph.D., Professor of Pharmacology and Chemistry; Director, Medicinal Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center

  • What are the potential therapeutic advantages of PAMs (besides receptor subtype selectivity) and how can we exploit these?
  • What is the meaning and relevance of the agonist activity that many PAMs exhibit in addition to their PAM activity in vitro? Is this an artifact of recombinant expression systems? Do mixed ago/PAMs have potential therapeutic advantages?
  • Can allosteric modulators be used to modulate signaling bias? Can a PAM approach be used to avoid receptor desensitization?
  • Are dynamic assays (specifically cAMP assays) different/better than accumulation assays for detecting allosteric modulators?
  • Can expect to discover a large number of native allosteric modulators in the coming years?

5:45 End of Day

 

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