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

• Published in: Journal of medicinal chemistry 2022-02, Vol.65 (3), p.1786-1807
• Main Authors: Li, Yueshan, Zhang, Liting, Yang, Ruicheng, Qiao, Zeen, Wu, Ming, Huang, Chong, Tian, Chenyu, Luo, Xinling, Yang, Wei, Zhang, Yun, Li, Linli, Yang, Shengyong
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Colorectal Neoplasms - drug therapy; Drug Discovery; Female; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Docking Simulation; Molecular Structure; Oxazepines - chemical synthesis; Oxazepines - metabolism; Oxazepines - pharmacokinetics; Oxazepines - therapeutic use; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00672

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[f]­[1,4]­oxazepin-5­(2H)-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 21k being the most active one (IC50: 0.026 ± 0.008 μM). This compound also displayed excellent selectivity for TNIK against 406 other kinases. Compound 21k could efficiently suppress CRC cell proliferation and migration in in vitro assays and exhibited considerable antitumor activity in the HCT116 xenograft mouse model. It also showed favorable pharmacokinetic properties. Overall, 21k could be a promising lead compound for drug discovery targeting TNIK and deserves further studies.