The key hypothesis of the MLSCN proposal is that high throughput chemical approaches, when integrated with state-of-the art post-genome sequence, cell, molecular and in vivo biology, provides a rapid and facile mechanism for enhancing the progress of biomedical science by the discovery of proof-of-concept (POC) molecules. Moreover, it POC molecule discovery will significantly speed up the application of biomedical advances to enhancing the public health and quality of life. Experimental efforts at TSRI and elsewhere have provided substantial peer-reviewed papers over the past 2 years that support the ability of these approaches to move fields forward with great rapidity. In addition, they exemplify the ability of a well integrated process to discover chemical probe molecules of exquisite selectivity, potency and in vivo efficacy, and to define novel biological targets. Compelling results emerge when modern high throughput chemical biology can be integrated with genetic approaches such as homologous recombinant deletion of target genes, or expression profiling of compounds with significant in vitro activity. These approaches have defined new key points of biological control in the regulation of lymphocyte recirculation and immunosuppression, as well as in neurogenesis. Assay expertise within TSRI has covered many different formats from whole cell calcium flux assays, reporter gene assays, enzyme assays, protein-protein interactions and cellular differentiation readouts. We further expect this approach to synergize with higher throughput molecular biological approaches such as siRNA, and therefore be a fundamental driver for scientific momentum in post-genome sequence biomedical science. The theme of the TSRI proposal is therefore the flexible, integrated discovery of proof-of-concept molecules across target classes, with an emphasis on GPCRs and pathways of cellular differentiation. We propose to do so by committing specifically to these three Specific Aims:
Aim #1 : Establish an Assay Implementation Group with the ability to optimize 20 assays per year during Years 2 and 3.
Aim #2 : Implement HTS to screen 20 assays and a minimum of 100,000 compounds per assay per year with transfer of the quality-assured data in a timely matter to PubChem database.
Aim #3 : development of pharmacokinetics and exploratory synthetic chemistry infrastructure to identify hits or hit-derived molecules capable of allowing biological proof of concept (POC) in cell-based systems or in vivo. Execution on these goals will provide community data, tools and resources for the dissemination of the tools of chemical biology to a broader segment of the biomedical research, thus enhancing the success and impact of the NIH Roadmap of measurable endpoints in human health. ? ?
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