Emergence of TNIK inhibitors in cancer therapeutics

Abstract

The outcome of patients with metastatic colorectal cancer remains unsatisfactory. To improve patient prognosis, it will be necessary to identify new drug targets based on molecules that are essential for colorectal carcinogenesis, and to develop therapeutics that target such molecules. The great majority of colorectal cancers (>90%) have mutations in at least one Wnt signaling pathway gene. Aberrant activation of Wnt signaling is a major force driving colorectal carcinogenesis. Several therapeutics targeting Wnt pathway molecules, including porcupine, frizzled receptors and tankyrases, have been developed, but none of them have yet been incorporated into clinical practice. Wnt signaling is most frequently activated by loss of function of the adenomatous polyposis coli (APC) tumor suppressor gene. Restoration of APC gene function does not seem to be a realistic therapeutic approach, and, therefore, only Wnt signaling molecules downstream of the APC gene product can be considered as targets for pharmacological intervention. Traf2 and Nck‐interacting protein kinase (TNIK) was identified as a regulatory component of the β‐catenin and T‐cell factor‐4 (TCF‐4) transcriptional complex. Several small‐molecule compounds targeting this protein kinase have been shown to have anti‐tumor effects against various cancers. An anthelmintic agent, mebendazole, was recently identified as a selective inhibitor of TNIK and is under clinical evaluation. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its pharmacological inhibition seems to be a promising therapeutic approach. We demonstrated the feasibility of this approach by developing a small‐molecule TNIK inhibitor, NCB‐0846.

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

“…A number of small-molecule compounds targeting TNIK, including mebendazole, an anthelmintic agent and selective inhibitor of TNIK (73), NCB-0846, a small-molecule TNIK inhibitor (73) and HI-B1, a small molecule that directly interacts with β-catenin (74), have been demonstrated to exert anti-tumor effects against various cancers. At present, mebendazole is under clinical evaluation (73). In addition, pyrvinium, a potent WNT inhibitor used as an anthelmintic drug, may also sensitize ovarian cancer cells to chemotherapy (75).…”

Identification of endogenous Adenomatous polyposis coli interaction partners and β-catenin-independent targets by proteomics

“…Importantly, these processes are also deregulated in APC mutant tissues (Wong et al, 1996; Mahmoud et al, 1997; Caldwell et al, 2007). Moreover, TRAF2 and NCK interacting protein kinase (TNIK), which shares high sequence homology with MINK1, is emerging as a promising target for CRC therapy, as it regulates the activity of the TCF-4/β-catenin transcription complex (Yamada and Masuda, 2017; Masuda, et al, 2016).…”

miR‑20b promotes growth of non‑small cell lung cancer through a positive feedback loop of the Wnt/β‑catenin signaling pathway

“…Based on the impact of Wnt/β-catenin signaling on cancer progression, anticancer drugs targeting the Wnt/β-catenin signaling pathway have attracted much attention (36). However, most Wnt signaling genes mutated in colorectal cancer, including APC, are tumor suppressors and cannot be directly targeted for therapeutic purposes (37). β-catenin is a proto-oncogene that is a ubiquitously expressed cell adhesion molecule and cannot be used as a drug target (37).…”

“…However, most Wnt signaling genes mutated in colorectal cancer, including APC, are tumor suppressors and cannot be directly targeted for therapeutic purposes (37). β-catenin is a proto-oncogene that is a ubiquitously expressed cell adhesion molecule and cannot be used as a drug target (37). Therefore, finding new molecules that play an important role in the inactivation of the Wnt/β-catenin signaling pathway has clinical application potential.…”