Open AccessDiscovery of Pyridazinone and Pyrazolo[1,5-a]pyridine Inhibitors of C-Terminal Src Kinase
Author(s) -
Daniel P. O’Malley,
Vijay T. Ahuja,
Brian E. Fink,
Carolyn Cao,
Cindy Wang,
Jesse Swanson,
Susan Wee,
Ashvinikumar V. Gavai,
John S. Tokarski,
David Critton,
Anthony Paiva,
Benjamin M. Johnson,
Nicolas Szapiel,
Dan Xie
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00354
Subject(s) - kinase , proto oncogene tyrosine protein kinase src , phosphorylation , tyrosine protein kinase csk , chemistry , regulator , in vitro , signal transduction , pharmacology , src family kinase , biochemistry , microbiology and biotechnology , cancer research , biology , sh3 domain , gene
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.