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 4 (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, in vitro and in vivo preclinical
studies revealed favorable in vitro and in
vivo DMPK properties. Results from multiple cell-based and
animal models proved that compound 4 exhibits considerable
antifibrotic and anti-inflammatory efficacy. Currently, phase II clinical
trials of compound 4 are underway for the treatment of
idiopathic pulmonary fibrosis (IPF).