Discovery of\nBis-imidazolecarboxamide Derivatives\nas Novel, Potent, and Selective TNIK Inhibitors for the Treatment\nof Idiopathic Pulmonary Fibrosis

Traf2- and Nck-interacting kinase\n(TNIK) has been identified\nas\na promising therapeutic target for the treatment of fibrosis-driven\ndiseases. Utilizing a structure-based drug design workflow, we developed\na series of potent TNIK inhibitors that modulate the conformation\nof the gatekeeper Met105 side chain and access the TNIK back pocket.\nThe lead optimization efforts culminated in the discovery of the recently\nreported compound <b>4</b> (INS018_055), a novel TNIK inhibitor.\nThis molecule demonstrated excellent activity in both enzymatic and\ncell-based assays, along with high selectivity in a kinome panel.\nFurther, <i>in vitro</i> and <i>in vivo</i> preclinical\nstudies revealed favorable <i>in vitro</i> and <i>in\nvivo</i> DMPK properties. Results from multiple cell-based and\nanimal models proved that compound <b>4</b> exhibits considerable\nantifibrotic and anti-inflammatory efficacy. Currently, phase II clinical\ntrials of compound <b>4</b> are underway for the treatment of\nidiopathic pulmonary fibrosis (IPF).