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

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 D. Westover, Tinghu Zhang, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 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.

Original languageEnglish (US)
Pages (from-to)1624-1641
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number4
StatePublished - Feb 27 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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