Day 1 | Day 2 | Download Brochure
Thursday, June 17
8:20 am Chairperson's Remarks
Terry Kenakin, Ph.D., Director, Biological Reagents and Assay Development, GlaxoSmithKline R&D
8:30 The Importance of Pharmacology in New Drug Discovery with Reference to Allosteric and Functionally Selective Molecules
Terry Kenakin, Ph.D., Director, Biological Reagents and Assay Development, GlaxoSmithKline R&D
The introduction of human genomic information has had undeniable impact on drug discovery but continued experience shows that the behavior of intact systems still holds the key to predicting potential therapeutic value in new drug molecules. Pharmacology is uniquely suited to quantifying drug behaviors in test systems and providing scales to predict subsequent effect in all systems including the therapeutic one. This presentation will highlight how pharmacology does this for allosteric drug molecules including those producing classic ‘guest’ allostery, receptor dimerization and especially functional selectivity. New pharmacological techniques can be used to reduce complex selective ligand profiles to numbers on scales amenable to use by medicinal chemists aimed at lead optimization. The promise of such endeavors is to link newly characterized allosteric selectivity with uniquely valuable phenotypic therapies in the clinic.
9:00 Functionally selective and context-dependent pharmacology of GPCR allosteric modulators
Colleen Niswender, Ph.D., Research Assistant Professor, Pharmacology, Vanderbilt University
Allosteric modulation is emerging as a novel strategy for regulating GPCR function. In addition to providing enhanced selectivity for a given target, allosteric compounds can exhibit improved pharmacokinetic properties versus orthosteric ligands. The ability of allosteric modulators to potentially interact with specific GPCR conformations, however, provides new layers of texture to receptor pharmacology. This presentation will address issues of functionally selective and context-dependent pharmacology induced by allosteric modulators with a focus on muscarinic and metabotropic glutamate receptors.
9:30 Precision Pharmacology: GPCR Biased Ligands Elicit Unique Signal Transduction Profiles
Scott DeWire, Ph.D., Senior Research Scientist & Co-Founder, Trevena, Inc.
Ligand bias at GPCRs is of rapidly growing interest to drug discovery. TRV001 is a potent, selective β-arrestin biased agonist at the AngII receptor. This compound exhibits antagonism for G protein activation, yet agonism for β-arrestin-mediated activities. In vivo, TRV001 also possesses a unique profile: reducing blood pressure while increasing cardiac output. These results solidify ligand bias as a mechanism to achieve differential physiological effects.
10:00 Networking Coffee Break, Poster and Exhibit Viewing
10:45 Identification of Novel GPCR Activators: Small Molecules and Superagonists
Alan S. Kopin, M.D., Professor of Medicine, Director, Molecular Pharmacology Research Center, Tufts Medical Center, Tufts University School of Medicine
To address the paucity of ligands for selected GPCRs we have utilized two different recombinant DNA approaches. To identify small molecule agonists, we utilize constitutively active receptors as hypersensitive probes. This strategy was successfully applied to structurally diverse GPCRs including receptors that are relatively refractory to synthetic ligand activation (e.g. the GLP-1 receptor). Compounds that are identified provide structural templates for further agonist optimization, enabling the development of small molecule agonists at the wild type receptor. As a complementary strategy to activate GPCRs, we have generated and utilized membrane tethered peptide ligands. These recombinant constructs encode a transmembrane domain anchor linked to an extracellular peptide ligand. We have shown that tethered ligands are highly efficacious, receptor selective, and can be engineered to have superagonist, agonist, or antagonist activity. Together our innovative tools offer a powerful means to enhance the understanding of GPCR mediated function.
11:15 Impact of Heterodimerization of GPCRs in Drug Discovery
Lakshmi Devi, Ph.D., Professor, Pharmacology and Systems Therapeutics, Professor, Psychiatry; Mount Sinai
G protein coupled receptor activity is regulated by a number of mechanisms. Among these, protein-protein interaction, and in particular, interactions with other receptors leading to heteromerization has been shown to play an important role. Emerging studies provide evidence for tissue-specific, disease-specific receptor heteromerization suggesting that heteromers represent novel drug targets for the identification of selective compounds with potentially reduced side-effects.
Sponsored by
(1).JPG?n=8495 "Millipore (updated)")
11:45 Luncheon Presentation Cell Based Assays for Lead Discovery
Jeff Till, Ph.D., Marketing Director, Drug Discovery, Millipore
The need for more biologically relevant applications that improve decision-making power for drug discovery has never been greater. Millipore’s innovative research and development programs continue to focus on meeting this need. A case study will be presented illustrating the latest applications for GPCR drug discovery, combining cellular imaging and stem cell-derived model systems.
1:15 pm Chairperson's Remarks
Lisa K. Minor, Ph.D.
1:25 BacMam: the solution to 7TM receptor and ligand-Gated ion channel assays
Elizabeth A. Davenport, Ph.D., Manager, Cell-Based Assay Development, Department of Biological Reagents and Assay Development, GlaxoSmithKline
BacMam viruses provide an unparalleled level of experimental flexibility that is simply not possible when using stable recombinant cell lines. Using BacMam technology, target gene expression levels may be quickly and easily optimized while simultaneously characterizing endogenous host cell responses. Delivery of multiple genes also is possible; for example, co-expression of a receptor and a G protein. Overall, BacMam offers a versatile target expression solution that translates to cost, time, and work flow savings throughout the process of reagent generation, assay development, and screening.
1:55 Parallel Screening of Target and Anti-Target Accelerates the Hit-To-Lead Effort
Peter Hodder, Ph.D., Senior Director, Lead Identification, Translational Research Institute, The Scripps Research Institute
Enabled by the lower costs of 1536-well format screening, Scripps has implemented a paradigm where an HTS target and its “anti-target” (artifact counterscreen, cytotoxicity assay, selectivity assay, etc.) are screened in parallel as primary screens. We have used this paradigm for several targets of therapeutic interest, in both cell-based and biochemical HTS campaigns. This presentation will focus on the selection of target/anti-target screening pairs that impact the discovery of relevant post-HTS leads. Scaffolds emerging from GPCR, transcription factor, ion channel and hydrolase parallel screening campaigns will be presented.
2:25 Ice Cream Refreshment Break in the Exhibit Hall
3:05 GPCR Assays for High Throughput and Ultra High Throughput Screening
Priya Kunapuli, Ph.D., Director, In Vitro Sciences, BRSO, Merck Research Laboratories
High throughput screening (HTS) is one of the first steps towards providing useful pharmaceutical leads for drug discovery. Recent increases in the size of drug archives and cost containment have become essential drivers of assay miniaturization for HTS and uHTS. For GPCR targets, miniaturization of cell-based assays to 1536- and 3456-well plate formats has been greatly enhanced by technological improvements in low volume pipetting devices and detection systems as well as the availability of a variety of functional assays interrogating receptor activity. The application and relative merits of these GPCR assays for identification of agonists, antagonists, allosteric modulators and biased ligands will be presented.
3:35 Application of Label-Free Assays for GPCR targets
Hong Xin, Ph.D., Senior Scientist, Lead Generation Biology, Johnson & Johnson, PRD
4:05 High Throughput Screening Strategies for the Identification of Allosteric Modulators of 7TM Receptors
John Watson, Ph.D., Lead Investigator, Bristol-Myers Squibb
Allosteric modulators of G protein-coupled receptors are expected to offer several advantages over orthosteric ligands for drug development, such as an improved selectivity, enhanced safety profiles, and maintenance of spatial and temporal aspects of signaling. However, before allosteric modulators can be developed as drugs, they must first be discovered by screening. This presentation will review some of our recent experiences with high throughput screens for positive allosteric modulators.
4:35 End of Conference
Day 1 | Day 2 | Download Brochure