Discovery of Bis-imidazolecarboxamide Derivatives as Novel, Potent, and Selective TNIK Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis

Traf2- and Nck-interacting kinase (TNIK) has been identified as a promising therapeutic target for the treatment of fibrosis-driven diseases. Utilizing a structure-based drug design workflow, we developed a series of potent TNIK inhibitors that modulate the conformation of the gatekeeper Met105 side chain and access the TNIK back pocket. The lead optimization efforts culminated in the discovery of the recently reported compound <b>4</b> (INS018_055), a novel TNIK inhibitor. This molecule demonstrated excellent activity in both enzymatic and cell-based assays, along with high selectivity in a kinome panel. Further, <i>in vitro</i> and <i>in vivo</i> preclinical studies revealed favorable <i>in vitro</i> and <i>in vivo</i> DMPK properties. Results from multiple cell-based and animal models proved that compound <b>4</b> exhibits considerable antifibrotic and anti-inflammatory efficacy. Currently, phase II clinical trials of compound <b>4</b> are underway for the treatment of idiopathic pulmonary fibrosis (IPF).