Discovery of 3,4-Dihydrobenzo[<i>f</i>][1,4]oxazepin-5(2<i>H</i>)-one Derivatives as a New Class of Selective TNIK Inhibitors and Evaluation of Their Anti-Colorectal Cancer Effects

Abstract

The Traf2- and Nck-interacting protein kinase (TNIK) is a downstream signal protein of the Wnt/β-catenin pathway and has been thought of as a potential target for the treatment of colorectal cancer (CRC) that is often associated with dysregulation of Wnt/β-catenin signaling pathway. Herein, we report the discovery of a series of 3,4-dihydrobenzo[<i>f</i>][1,4]oxazepin-5(2<i>H</i>)-one derivatives as a new class of TNIK inhibitors. Structure-activity relationship (SAR) analyses led to the identification of a number of potent TNIK inhibitors with compound <b>21k</b> being the most active one (IC₅₀: 0.026 ± 0.008 μM). This compound also displayed excellent selectivity for TNIK against 406 other kinases. Compound <b>21k</b> could efficiently suppress CRC cell proliferation and migration in <i>in vitro</i> assays and exhibited considerable antitumor activity in the HCT116 xenograft mouse model. It also showed favorable pharmacokinetic properties. Overall, <b>21k</b> could be a promising lead compound for drug discovery targeting TNIK and deserves further studies.