Discovery and validation of new kinase drug targets in T. brucei

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Human African trypanosomiasis (HAT) is a potentially fatal disease caused by the parasite Trypanosoma brucei. Archaic drugs, with unacceptable toxicity (5% fatality), are often used for the treatment of HAT. Disease relapse and drug resistance are also common and increasing in prevalence. In identifying new drug targets for neglected diseases, members of enzyme families that have been successfully drugged for other diseases are highly attractive due to the ready availability of family - targeted pharmacophores and existing medicinal chemistry knowledge. Over the last 15 years, protein kinases have emerged as highly promising drug targets, with 22 small molecules that inhibit members of this enzyme family approved for clinical use. While genetic approaches in T. brucei have demonstrated the essentiality of several of the ~170 PKs in this organism, none of these kinases have been pharmacologically validated. In this project, we propose to use a forward chemical genetic approach to identify druggable protein kinases in T. brucei. By identifying the intra - cellular kinase targets of a small molecule inhibitor that potently blocks the growth of th bloodstream form (BSF) of T. brucei, we will identify and validate kinases that are highly susceptible to targeted inhibition. Parallel medicinal chemistry efforts will be used to generate ATP - competitive inhibitors with improved potency and selectivity. The outcome of this project will be to chemically validate multiple protein kinases as drug targets for HAT and VL.