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Abstract C013: HI-B9 suppresses colorectal cancer by inhibiting Wnt/β-catenin pathway

Deregulated Wnt/β-catenin pathway plays an important role in colorectal cancer. β-Catenin interacts with transcription factor 7-like 2 (TCF7L2 or TCF4) to express oncogenes including c-myc, axin2 and cyclin D1. Here we describe a small molecule, referred to as HI-B9, which inhibits the growth of colorectal cancer cell lines. HI-B9 suppressed tryptophan fluorescence of β-catenin that contains TCF4-binding residues. In silico docking of HI-B9 on β-catenin showed a binding mode that blocks Lys 312 residue which is critical for the interaction between β-catenin and its interactors. A binding assay showed that the binding affinity of HI-B9 against β-catenin G307A/K312E mutant was significantly reduced compared to that against wildtype. HI-B9 inhibited β-catenin/TCF4 luciferase activity in a dose-dependent manner. Anchorage-independent growth of HCT116 and HT29 colorectal cancer cells were suppressed by the small molecule. mRNA expression levels of Wnt target genes were reduced by HI-B9 treatment. HI-B9 did not affect the translocation of β-catenin toward the nucleus. The therapeutic effects of HI-B9 was due to the disruption of β-catenin/TCF4 complex formation ex vivo. Our findings demonstrate the therapeutic potential of HI-B9 against colorectal cancer with aberrant Wnt/β-Catenin signaling pathway. Citation Format: Seung Ho Shin, Kanamata Reddy, Zigang Dong. HI-B9 suppresses colorectal cancer by inhibiting Wnt/β-catenin pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C013. doi:10.1158/1535-7163.TARG-19-C013