The overall goal of the combinatorial chemistry section (Project 1) of this Program Project grant application is the demonstration of new strategies for mechanism-based anticancer drug discovery using solid-phase and solution-phase combinatorial synthesis as well as phase-switching methods. Lead structure identification is mainly derived from natural products and target-based array design. High quality, defined-compound libraries will provide the broad structure-activity relationship necessary for rational lead optimization. Specifically, we have four major strategic goals: 1. to develop solution-phase and solid-phase parallel synthesis protocols for the preparation of a focused library of ca. 200 peptide mimetics based on rational design and the co-crystal of human Cdc25B and a peptide ligand, 2. the design of novel phosphate group mimics with the goal of identifying new scaffolds for highly selective protein phosphatase inhibitors, 3. to prepare a library of ca. 500 analogs of the femtomolar antimitotic agent tubulysin A with the goal to develop selective anticancer agents that target microtubule assembly, 4. to explore new synthetic methods for the preparation and analysis of novel dynamic libraries for phosphatase inhibition and the discovery of new classes of antiproliferative agents. The proposed program represents a multi-dimensional effort to improve current methodologies for the combinatorial synthesis of organic molecules, establish new strategies for the use of natural products as lead structures for drug discovery, and identify novel mechanism-based anticancer agents.
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