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.

中文翻译：

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基于结构的针对 P 环半胱氨酸的 SRC 激酶有效选择性共价抑制剂的设计。

SRC 是许多信号通路的主要调节者，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，我们描述了我们通过靶向 SRC P 环上的半胱氨酸 277 来开发选择性 SRC 共价抑制剂的努力。使用混杂的共价激酶抑制剂 (CKI) SM1-71 作为起点，我们开发了共价抑制剂 15a，它将 SRC 与 SM1-71 的其他共价靶标（包括 TAK1 和 FGFR1）区分开来。作为不可逆共价抑制剂，化合物 15a 在体外和体内均表现出对 SRC 信号传导的持续抑制。此外，15a 在具有 SRC 激活的非小细胞肺癌细胞系中表现出有效的抗增殖作用，从而提供了证据表明这种方法可能有望用于进一步的药物开发工作。