Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity
Lih-Yun Hsu, James T. Rosenbaum, Erik Verner, William B. Jones, Craig Hill, James W. Janc, Joseph J. Buggy, Rahul D. Pawar, Poorva Ghosh, Dan Li, Ning Ding, John Reneau, Michael S. Khodadoust, Youn H. Kim, Ryan A. Wilcox, Richard A. Miller
Abstract
ITK is a kinase involved in T cell activation, proliferation and differentiation. In mice, selective knock-out of the ITK gene produces Th1 skewing of T helper cell differentiation. Soquelitinib, a covalent ITK inhibitor, blocks ITK activity with greater than 100-fold selectivity compared to inhibition of a related kinase, RLK. We describe the chemistry and biologic effects of soquelitinib. In vitro studies with normal or malignant T cells demonstrated that soquelitinib suppresses Th2 cytokine production preferentially with relative sparing of Th1 cytokines. Soquelitinib inhibits the in vivo growth of several syngeneic murine tumors including those that do not express ITK. Treatment with soquelitinib leads to increased tumor infiltration of normal CD8+ cells that possess enhanced T effector function. Soquelitinib reduced expression of T cell exhaustion markers and was able to restore T effector function to exhausted cells. Pharmacologic selective ITK inhibition may represent a novel approach to cancer immunotherapy.