Wang Tiansheng, Bemis Guy, Hanzelka Brian, Zuccola Harmon, Wynn Michael, Moody Cameron Stuver, Green Jeremy, Locher Christopher, Liu Aixiang, Gao Hongwu, Xu Yuzhou, Wang Shaohui, Wang Jie, Bennani Youssef L, Thomson John A, Müh Ute
Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States.
Shanghai ChemPartner Co. Ltd., 998 Halei Road, Pudong New Area, Shanghai 201203, China.
ACS Med Chem Lett. 2017 Nov 28;8(12):1224-1229. doi: 10.1021/acsmedchemlett.7b00239. eCollection 2017 Dec 14.
Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in . Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition ( ≈ 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 μM (1-2 μg/mL) against the H37Ra isolate of .
耐多药结核病感染正在增加，通过新机制发挥抑制作用的抗生素可能是不断发展的结核病治疗的重要组成部分。蛋白激酶A（PknA）和蛋白激酶B（PknB）都是结核分枝杆菌中必需的丝氨酸 - 苏氨酸激酶。鉴于激酶抑制方面有广泛的知识库，这些酶为抗分枝杆菌药物发现提供了一个有趣的机会。本研究专注于靶向PknA和PknB，同时提高对相关哺乳动物激酶的选择性窗口。化合物对PknA和PknB均实现了强效抑制（≈5 nM）。鉴定出了分枝杆菌激酶特有的结合口袋。填充该口袋的取代导致对多种哺乳动物激酶有100倍的差异。降低亲脂性可提高抗分枝杆菌活性，最有效的化合物对结核分枝杆菌H37Ra菌株的最低抑菌浓度范围为3至5 μM（1 - 2 μg/mL）。
