Discovery of Pyridazinone and Pyrazolo[1,5- a]pyridine Inhibitors of C-Terminal Src Kinase

  • ACS Med Chem Lett. 2019 Sep 25;10(10):1486-1491. doi: 10.1021/acsmedchemlett.9b00354.
Daniel P O'Malley  1 ,  Vijay Ahuja  1 ,  Brian Fink  1 ,  Carolyn Cao  1 ,  Cindy Wang  1 ,  Jesse Swanson  1 ,  Susan Wee  1 ,  Ashvinikumar V Gavai  1 ,  John Tokarski  1 ,  David Critton  1 ,  Anthony A Paiva  1 ,  Benjamin M Johnson  1 ,  Nicolas Szapiel  1 ,  Dianlin Xie  1
Affiliations
  • 1. Bristol-Myers Squibb Company, Research and Development, Route 206 and Province Line Road, Princeton, New Jersey 08543, United States.
PMID: 31620238 DOI: 10.1021/acsmedchemlett.9b00354
Abstract

C-terminal Src kinase (Csk) functions as a negative regulator of T cell activation through inhibitory phosphorylation of Lck, so inhibitors of Csk are of interest as potential immuno-oncology agents. Screening of an internal kinase inhibitor collection identified pyridazinone lead 1, and a series of modifications led to optimized compound 13. Compound 13 showed potent activity in biochemical and cellular assays in vitro and demonstrated the ability to increase T cell proliferation induced by T cell receptor signaling. Compound 13 gave extended exposure in mice upon oral dosing and produced a functional response (decrease in Lck phosphorylation) in mouse Spleens at 6 h post dose.

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