The overall goal of this renewal application for a Chemical-Biology Interface Program Project is to generate novel chemical libraries based on potent natural product-derived pharmacophores and to identify promising new lead structures that affect cancer-relevant molecular targets. In this translational application, we intend to exploit recent advances in solid phase and solution phase combinatorial chemistry developed in our laboratories to synthesize unique natural product-based, small-molecular libraries. Our synthetic efforts are focused on two highly relevant molecular targets for solid tumors: (a) microtubules/tubulin, which is an established critical target for several clinically active anticancer agents, including the taxanes and vinca alkaloids, and (b) dual specificity phosphatases that have been documented to be novel proto-oncogenes and regulators of cell cycle progression and apoptosis. In addition to in vitro biochemical assays, we propose to develop and employ novel cellular assays that will be applicable to a wide variety of cancer-related signal transduction and cell structural targets. A highly innovative dynamic combinatorial library approach will also be undertaken to probe new chemical structures and to provide a unique chemical platform for future compound generation. Enhancement and expansion of the fundamental bioisosteres will occur with the assistance of the Bioinformation and Cell-based Assay Core, which will also maintain the central chemical and biological database. Our Preclinical Evaluation Core will evaluate the pharmacodynamics and pharmacokinetics of prioritized compounds in relevant mouse models. Our overall hypothesis is that novel; structurally unique, lead antineoplastic agents can be generated and identified by an integrated use of contemporary combinatorial chemistry, biochemistry, pharmacology, cell biology and informatics.
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