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.

Public Health Relevance

Drug resistance and toxicity are increasingly leading to treatment failures for African sleeping sickness, which is fatal if left untreated. This projectwill use forward chemical genetics to identify druggable protein kinases from the causative agent Trypanosoma brucei. These protein kinase targets will be validated with potent and selective pharmacological agents. Thus, our project will identify and validate new targets that can be used for treatment of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI110743-01
Application #
8673373
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$404,853
Indirect Cost
$154,853
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195