Structural Insight into TNIK Inhibition
- Int J Mol Sci. 2022 Oct 27;23(21):13010. doi: 10.3390/ijms232113010.
- 1. Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
- 2. Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
TRAF2- and NCK-interacting kinase (TNIK) has emerged as a promising therapeutic target for colorectal Cancer because of its essential role in regulating the Wnt/β-catenin signaling pathway. Colorectal cancers contain many mutations in the Wnt/β-catenin signaling pathway genes upstream of TNIK, such as the adenomatous polyposis coli (APC) tumor suppressor gene. TNIK is a regulatory component of the transcriptional complex composed of β-catenin and T-cell factor 4 (TCF4). Inhibition of TNIK is expected to block the aberrant Wnt/β-catenin signaling caused by colorectal Cancer mutations. Here we present structural insights into TNIK inhibitors targeting the ATP-binding site. We will discuss the effects of the binding of different chemical scaffolds of nanomolar inhibitors on the structure and function of TNIK.