2. Academic Validation
  3. Structure-Based Design of a Potent and Selective Covalent Inhibitor for SRC Kinase That Targets a P-Loop Cysteine

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

  • J Med Chem. 2020 Feb 27;63(4):1624-1641. doi: 10.1021/acs.jmedchem.9b01502.
Guangyan Du 1 2,  Suman Rao 1 2 3,  Deepak Gurbani 4,  Nathaniel J Henning 1 2,  Jie Jiang 1 2,  Jianwei Che 1 2,  Annan Yang 5,  Scott B Ficarro 1,  Jarrod A Marto 1,  Andrew J Aguirre 5,  Peter K Sorger 3,  Kenneth D Westover 4,  Tinghu Zhang 1 2,  Nathanael S Gray 1 2
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 2 Department of Cancer Biology , Dana Farber Cancer Institute , 450 Brookline Avenue , Boston , Massachusetts 02215 , United States.
  • 3 Laboratory of Systems Biology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 4 Departments of Biochemistry and Radiation Oncology , The University of Texas Southwestern Medical Center at Dallas , Dallas , Texas 75390 , United States.
  • 5 Department of Medical Oncology , Dana Farber Cancer Institute , 450 Brookline Avenue , Boston , Massachusetts 02215 , United States.
PMID: 31935084 DOI: 10.1021/acs.jmedchem.9b01502
Abstract

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.

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