Proof of concept molecules and molecular probes in drug discovery

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This proposal describes several of the projects planned or ongoing in our labs on design of chemical probes and optimized proof of concept (PoC) molecules for disease target discovery, validation and drug discovery. An associated project to develop new methods for enantioselective synthesis to facilitate lead optimization is also presented. 1) Leukotrienes (LTs) are implicated in a number of diseases and more recently are postulated to play an important role in inflammatory components of cardiovascular diseases. Inhibitors of LT biosynthesis have been associated with adverse effects which limit their use. A new class of "anomalous" inhibitors of leukotriene biosynthesis has recently been discovered whose mechanism of action is not understood. Optimized compounds in this class may exhibit a better chronic safety and tolerability profile. We plan to make affinity probes to identify the molecular target(s) on these compounds in the cell. Identification will allow a better understanding of the fundamental details of mechanism and controls of LT biosynthesis and the potential of inhibitors in this new class as new therapies. This research will also provide the assay tools necessary to optimize such inhibitors to identify viable development compounds. 2) As many compounds in the class of LT inhibitors have activity associated with a single enantiomer at a quaternary aryl chiral center, we plan to develop new and versatile methods for direct synthesis of such molecules based on ortho-directed metalation mediated by novel chiral silyldiamines and aminosiloxanes. Such methods will have broad applicability in organic synthesis. 3) Serine-threonine kinases form a large and highly homologous class of enzymes involved in many cellular processes and implicated in a wide variety of diseases. Selectivity has been an important problem in the development of such inhibitors. We plan to develop tools to assess kinase expression (in normal and diseased tissue) and selectivity of inhibition in cells. These tools will be based on affinity probes derived from the pan-selective kinase inhibitor staurosporine and analogs. Such tools will provide kinase expression maps and enzyme occupancy assays to enable drug discovery and optimization.