Structure-based design of a potent and selective covalent inhibitor for SRC kinase that targets a p-Loop cysteine.

07:00 EST 14th January 2020 | BioPortfolio

Summary of "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 multi-targeted 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 demonstrates 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.


Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804


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