Structure and Characterization of a Covalent Inhibitor of Src Kinase

Deepak Gurbani, Guangyan Du, Nathaniel J. Henning, Suman Rao, Asim K. Bera, Tinghu Zhang, Nathanael S. Gray, Kenneth D. Westover

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Unregulated Src activity promotes malignant processes in cancer, but no Src-directed targeted therapies are used clinically, possibly because early Src inhibitors produce off-target effects leading to toxicity. Improved selective Src inhibitors may enable Src-directed therapies. Previously, we reported an irreversible Src inhibitor, DGY-06-116, based on the hybridization of dasatinib and a promiscuous covalent kinase probe SM1-71. Here, we report biochemical and biophysical characterization of this compound. An x-ray co-crystal structure of DGY-06-116: Src shows a covalent interaction with the kinase p-loop and occupancy of the back hydrophobic kinase pocket, explaining its high potency, and selectivity. However, a reversible analog also shows similar potency. Kinetic analysis shows a slow inactivation rate compared to other clinically approved covalent kinase inhibitors, consistent with a need for p-loop movement prior to covalent bond formation. Overall, these results suggest that a strong reversible interaction is required to allow sufficient time for the covalent reaction to occur. Further optimization of the covalent linker may improve the kinetics of covalent bond formation.

Original languageEnglish (US)
Article number81
JournalFrontiers in Molecular Biosciences
StatePublished - May 19 2020


  • cancer
  • dasatinib
  • irreversible inhibitor
  • selectivity
  • src kinase

ASJC Scopus subject areas

  • Biochemistry
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Molecular Biology


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