2. Academic Validation
  3. Discovery of Pyridazinone and Pyrazolo[1,5- a]pyridine Inhibitors of C-Terminal Src Kinase

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

Affiliation

  • 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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