Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P-Loop Cysteine
Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P-Loop Cysteine
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基于结构设计一种以P-环半胱氨酸为靶点的SRC激酶有效选择性共价抑制剂
DOI：
10.1021/acs.jmedchem.9b01502
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发表时间：
2020-02-27
影响因子：
7.3
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
--
作者：
Du, Guangyan;Rao, Suman;Gray, Nathanael S.
SRC是许多信号通路的主要调节因子，并有助于癌症的发展。然而，选择性SRC抑制剂的开发一直具有挑战性，FDA批准的SRC抑制剂达沙替尼和博舒替尼是多靶点激酶抑制剂。在这里，我们描述了我们的努力，以开发一种选择性SRC共价抑制剂，靶向半胱氨酸277的P-环的SRC。使用混杂的共价激酶抑制剂（CKI）SM 1 -71作为起点，我们开发了共价抑制剂15 a，其将SRC与包括TAK 1和FGFR 1的SM 1 -71的其他共价靶区分开。作为不可逆共价抑制剂，化合物15 a在体外和体内均表现出持续的SRC信号传导抑制。此外，15 a在具有SRC活化的非小细胞肺癌细胞系中表现出有效的抗增殖作用，从而提供证据表明这种方法可能有希望用于进一步的药物开发工作。
SRC is a major regulator of many signaling pathways and contributes to cancer development. However, development of a selective SRC inhibitor has been challenging, and FDA-approved SRC inhibitors, dasatinib and bosutinib, are multitargeted kinase inhibitors. Here, we describe our efforts to develop a selective SRC covalent inhibitor by targeting cysteine 277 on the P-loop of SRC. Using a promiscuous covalent kinase inhibitor (CKI) SM1-71 as a starting point, we developed covalent inhibitor 15a, which discriminates SRC from other covalent targets of SM1-71 including TAK1 and FGFR1. As an irreversible covalent inhibitor, compound 15a exhibited sustained inhibition of SRC signaling both in vitro and in vivo. Moreover, 15a exhibited potent antiproliferative effects in nonsmall cell lung cancer cell lines harboring SRC activation, thus providing evidence that this approach may be promising for further drug development efforts.