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Diversity Oriented Synthesis of Protein Kinase Inhibitors


Protein kinases (PKs) are important regulators of cellular networks but our current understanding of the role of individual kinases is in part limited by our ability to measure and modulate their activity. In this respect, small molecule inhibitors are va luable tools. The project proposes to synthesize a focused library targeted towards PKs that is based on two potent and selective natural products, a MEK and a TAK1 inhibitor. These two kinases are important therapeutic targets as the activity of MEK has been identified in a number of cancers and TAK1 is important in the inflammation pathway. The library could prove valuable in improving the activity of these natural leads but perhaps more importantly, could extend to the discover of new inhibitors agains t "orphan kinases". First, a concise synthesis using solution phase and solid phase chemistry is proposed to access to both natural products from a common late stage intermediate. Importantly, the proposed chemistry is amenable to library synthesis. A strong emphasis will be put on the use of molecular modeling to evaluate library diversity and conformational diversity of the library. Second, based on the optimized chemistry developed towards the natural product, and the selected point of diversity ide ntified from modeling, the library will be synthesized. The host laboratory is developing microarray based profiling methods to assess kinase inhibitors on a proteomic scale. The library will be evaluated using this kinase profiling technology as well as a more traditional assay.

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