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.DOI: https://doi.org/10.1021/acs.jmedchem.9b01502
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.
