Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P-Loop Cysteine

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) <b>SM1-71</b> as a starting point, we developed covalent inhibitor <b>15a</b>, which discriminates SRC from other covalent targets of <b>SM1-71</b> including TAK1 and FGFR1. As an irreversible covalent inhibitor, compound <b>15a</b> exhibited sustained inhibition of SRC signaling both <i>in vitro</i> and <i>in vivo</i>. Moreover, <b>15a</b> 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.