Discovery of Pyridazinone and Pyrazolo[1,5-a]pyridine Inhibitors of C-Terminal Src Kinase.
Basic Information
ID: ALA4304837
Journal: ACS Med Chem Lett
Title: Discovery of Pyridazinone and Pyrazolo[1,5-a]pyridine Inhibitors of C-Terminal Src Kinase.
Authors: O'Malley DP, Ahuja V, Fink B, Cao C, Wang C, Swanson J, Wee S, Gavai AV, Tokarski J, Critton D, Paiva AA, Johnson BM, Szapiel N, Xie D.
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.
CiteXplore: 31620238
DOI: 10.1021/acsmedchemlett.9b00354
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