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

描述（由申请人提供）：非洲人类锥虫病（HAT）是一种由布鲁氏锥虫引起的潜在致命疾病。具有不可接受毒性（5%致死率）的古老药物常用于治疗HAT。疾病复发和耐药也很常见，而且发病率在增加。在确定被忽视疾病的新药物靶点时，由于家族靶向药物载体的现成可用性和现有的药物化学知识，已经成功用于其他疾病的酶家族成员具有很高的吸引力。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种抑制该酶家族成员的小分子被批准用于临床。虽然布鲁氏体的遗传方法已经证明了该生物中约170个PKs中的几个激酶的重要性，但这些激酶都没有得到药理学验证。在本项目中，我们建议使用正向化学遗传学方法来鉴定布鲁氏体中的“可药物”蛋白激酶。通过鉴定一种小分子抑制剂的细胞内激酶靶点，该抑制剂能有效阻断布鲁氏杆菌血流形式（BSF）的生长，我们将鉴定并验证对靶向抑制高度敏感的激酶。平行药物化学的努力将用于产生ATP竞争性抑制剂与提高效力和选择性。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.