thiohydantoins and Colorectal-Neoplasms

Both the Wnt/β-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. Inhibition of these signaling may therefore be an ideal strategy for treating CRC. We identified KY1220, a compound that destabilizes both β-catenin and Ras, via targeting the Wnt/β-catenin pathway, and synthesized its derivative KYA1797K. KYA1797K bound directly to the regulators of G-protein signaling domain of axin, initiating β-catenin and Ras degradation through enhancement of the β-catenin destruction complex activating GSK3β. KYA1797K effectively suppressed the growth of CRCs harboring APC and KRAS mutations, as shown by various in vitro studies and by in vivo studies using xenograft and transgenic mouse models of tumors induced by APC and KRAS mutations. Destabilization of both β-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other type cancers activated Wnt/β-catenin and Ras pathways.

Topics: Animals; Axin Protein; beta Catenin; Binding Sites; Cell Proliferation; Colorectal Neoplasms; Genes, APC; Genes, ras; Humans; Mice; Mice, Transgenic; Neoplasms, Experimental; Protein Stability; Proto-Oncogene Proteins p21(ras); RGS Proteins; Small Molecule Libraries; Thiohydantoins; Wnt Signaling Pathway

APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis. As shown by in vitro and in vivo studies using APCMin/+/K-RasG12DLA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. A small molecular approach degrading both β-catenin and Ras via inhibition of the Wnt/β-catenin signaling would be an ideal strategy for treatment of mCRC.

Topics: Actin Cytoskeleton; Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Epithelial-Mesenchymal Transition; Genes, APC; HEK293 Cells; Humans; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neoplasm Invasiveness; Protein Stability; Proteolysis; Proto-Oncogene Proteins p21(ras); Thiohydantoins; Time Factors; Wnt Signaling Pathway