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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.

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This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804
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