Discovery of Pyridazinone and Pyrazolo[1,5-<i>a</i>]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 <b>1</b>, and a series of modifications led to optimized compound <b>13</b>. Compound <b>13</b> showed potent activity in biochemical and cellular assays <i>in vitro</i> and demonstrated the ability to increase T cell proliferation induced by T cell receptor signaling. Compound <b>13</b> 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.