2. Academic Validation
  3. Inhibition of Wnt Signaling in Colon Cancer Cells via an Oral Drug that Facilitates TNIK Degradation

Inhibition of Wnt Signaling in Colon Cancer Cells via an Oral Drug that Facilitates TNIK Degradation

  • Mol Cancer Ther. 2023 Jan 3;22(1):25-36. doi: 10.1158/1535-7163.MCT-21-0801.
Kun Zhou 1,  Jae Eun Cheong 2,  Subrahmanian Tarakkad Krishnaji 3,  Aram Ghalali 3,  Haojie Fu 3,  Lufei Sui 3,  Catherine Alix-Panabières 4,  Laure Cayrefourcq 4,  Diane Bielenberg 3,  Lijun Sun 5,  Bruce Zetter 3
Affiliations

Affiliations

  • 1 Luye Pharma Boston R&D, Woburn, Massachusetts.
  • 2 Silicon Therapeutics, Boston, Massachusetts.
  • 3 Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 4 The University of Montpellier, Montpellier, France.
  • 5 Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
PMID: 36302395 DOI: 10.1158/1535-7163.MCT-21-0801
Abstract

We have synthesized an oxetane derivative of the benzimidazole compound mebendazole (OBD9) with enhanced solubility and strong Anticancer activity in multiple types of Cancer cells, especially colorectal Cancer. In this report, we provide evidence that OBD9 suppresses colorectal Cancer growth by interfering with the Wnt signaling pathway, a main driver of cell growth in colorectal Cancer. 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 colorectal Cancer.

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