Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation

• Published in: Nature chemical biology Vol. 12; no. 8; pp. 593 - 600
• Main Authors: Cha, Pu-Hyeon, Cho, Yong-Hee, Lee, Sang-Kyu, Lee, JaeHeon, Jeong, Woo-Jeong, Moon, Byoung-San, Yun, Ji-Hye, Yang, Jee Sun, Choi, Sooho, Yoon, Juyong, Kim, Hyun-Yi, Kim, Mi-Yeon, Kaduwal, Saluja, Lee, Weontae, Min, Do Sik, Kim, Hoguen, Han, Gyoonhee, Choi, Kang-Yell
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2016
• Subjects: 49/47; 631/67/1059; 631/80/86; 631/92/507; 631/92/613; Animals; Axin Protein - chemistry; Axin Protein - metabolism; beta Catenin - chemistry; beta Catenin - metabolism; Binding Sites; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Cell Proliferation - drug effects; Chemistry; Chemistry/Food Science; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Genes, APC; Genes, ras; Humans; Mice; Mice, Transgenic; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Neoplasms, Experimental - pathology; Protein Stability - drug effects; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; RGS Proteins - chemistry; RGS Proteins - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Thiohydantoins - chemical synthesis; Thiohydantoins - chemistry; Thiohydantoins - pharmacology; Wnt Signaling Pathway - drug effects
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.2103

A small-molecule compound binds to the RGS domain of axin, promotes the degradation of β-catenin and Ras through the GSK3β-mediated destruction complex, and reduces the growth of KRAS and APC mutant colorectal cancer cell lines. 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.