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How to prioritize T. brucei kinases and quantify their intracellular engagement by small-molecule inhibitors remain unsolved problems. Here, we combine chemoproteomics and RNA interference to interrogate trypanosome kinases bearing a Cys-Asp-Xaa-Gly motif (CDXG kinases). We discovered that hypothemycin, a fungal polyketide previously shown to covalently inactivate a subset of human CDXG kinases, kills T. brucei in culture and in infected mice. Quantitative chemoproteomic analysis with a hypothemycin-based probe revealed the relative sensitivity of endogenous CDXG kinases, including TbGSK3short and a previously uncharacterized kinase, TbCLK1. RNAi-mediated knockdown demonstrated that both kinases are essential, but only TbCLK1 is fully engaged by cytotoxic concentrations of hypothemycin in intact cells. Our study identifies TbCLK1 as a therapeutic target for African trypanosomiasis and establishes a new chemoproteomic tool for interrogating CDXG kinases in their native context.<\/jats:p>","DOI":"10.7554\/elife.00712","type":"journal-article","created":{"date-parts":[[2013,7,9]],"date-time":"2013-07-09T13:09:31Z","timestamp":1373375371000},"source":"Crossref","is-referenced-by-count":41,"title":["Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei"],"prefix":"10.7554","volume":"2","author":[{"given":"Mari","family":"Nishino","sequence":"first","affiliation":[{"name":"Tetrad Graduate Program, University of California, San Francisco, San Francisco, United States"},{"name":"Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan W","family":"Choy","sequence":"additional","affiliation":[{"name":"Chemistry 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