Guangyan Du, Suman Rao, Deepak Gurbani, Nathaniel J. Henning, Jie Jiang, Jianwei Che, Annan Yang, Scott B Ficarro, Jarrod A. Marto, Andrew J. Aguirre, Peter K. Sorger, Kenneth Dale Westover, Tinghu Zhang, and Nathanael S Gray.J. Med. Chem. 2020.
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 anti-proliferative effects in non-small cell lung cancer cell lines harboring SRC activation, thus providing evidence that this approach may be promising for further drug development efforts.