Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer

Eur J Med Chem. 2024 Feb 24;268:116240. doi: 10.1016/j.ejmech.2024.116240. Online ahead of print.ABSTRACTTraf2-and Nck-interacting protein kinase (TNIK) plays an important role in regulating signal transduction of the Wnt/β-catenin pathway and is considered an important target for the treatment of colorectal cancer. Inhibiting TNIK has potential to block abnormal Wnt/β-catenin signal transduction caused by colorectal cancer mutations. We discovered a series of 6-(1-methyl-1H-imidazole-5-yl) quinoline derivatives as TNIK inhibitors through Deep Fragment Growth and virtual screening. Among them, 35b exhibited excellent TNIK kinase and HCT116 cell inhibitory activity with IC50 values of 6 nM and 2.11 μM, respectively. 35b also shown excellent kinase selectivity, PK profiles, and oral bioavailability (84.64%). At a p. o. dosage of 50 mg/kg twice daily 35b suppressed tumor growth on the HCT116 xenograft model. Taken together, 35b is a promising lead compound of TNIK inhibitors, which merits further investigation.PMID:38422698 | DOI:10.1016/j.ejmech.2024.116240

Source: European Journal of Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Yaxin Teng Rui Wu Weichen Bo Minghai Tang TaiJin Wang Xue Cui Yong Li Chufeng Zhang Ziyan Ma Zhiyuan Fu Qing Xu Jie Liu Lijuan Chen Source Type: research