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

描述（由申请方提供）：非洲人锥虫病（HAT）是一种由寄生虫布氏锥虫引起的潜在致死性疾病。HAT的治疗通常使用毒性不可接受（5%的死亡率）的药物。疾病复发和抗药性也很常见，而且发病率不断上升。在鉴定用于被忽视疾病的新药物靶标时，由于家族靶向药效团的现成可用性和现有的药物化学知识，已经成功地对其他疾病进行药物治疗的酶家族的成员是非常有吸引力的。在过去的15年里，蛋白激酶已经成为非常有前途的药物靶点，有22种抑制这种酶家族成员的小分子被批准用于临床。而T.布氏杆菌已经证明了该生物体中约170种PK中的几种的重要性，但这些激酶中没有一种被证实是有效的。在这个项目中，我们建议使用正向化学遗传学方法来鉴定T。布鲁塞。通过鉴定小分子抑制剂的细胞内激酶靶点，该小分子抑制剂有效地阻断T血流形式（BSF）的生长。在布鲁氏菌中，我们将鉴定和验证对靶向抑制高度敏感的激酶。平行的药物化学努力将用于产生具有改进的效力和选择性的ATP竞争性抑制剂。该项目的结果将是化学验证多种蛋白激酶作为HAT和VL的药物靶点。

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.