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

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.

SUBMITTER: O'Malley DP

PROVIDER: S-EPMC6792176 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

O'Malley Daniel P DP Ahuja Vijay V Fink Brian B Cao Carolyn C Wang Cindy C Swanson Jesse J Wee Susan S Gavai Ashvinikumar V AV Tokarski John J Critton David D Paiva Anthony A AA Johnson Benjamin M BM Szapiel Nicolas N Xie Dianlin D

ACS medicinal chemistry letters 20190925 10

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 ...[more]

PMID: 31620238

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