Inhibition of Wnt signaling in colon cancer cells via an oral drug that facilitates TNIK degradation.

We have synthesized an oxetane derivative of the benzimidazole compound mebendazole (OBD9) with enhanced solubility and strong anti-cancer activity in multiple types of cancer cells, especially colorectal cancer (CRC). In this report, we provide evidence that OBD9 suppresses CRC growth by interfering with the Wnt signaling pathway, a main driver of cell growth in CRC. Specifically, we find that OBD9 induces autophagic degradation of TNIK (traf2 and Nck- interacting kinase), which promotes T cell factor-4 (TCF4)/beta-catenin-mediated gene expression. Thus, OBD9 as a TNIK inhibitor blocks Wnt/beta-catenin signaling at the final step of transcriptional activation. We suggest that OBD9 provides a potential novel autophagy-mediated, Wnt-damping therapeutic strategy for the treatment of CRC.