2. Academic Validation
  3. Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation

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

  • Nat Chem Biol. 2016 Aug;12(8):593-600. doi: 10.1038/nchembio.2103.
Pu-Hyeon Cha 1 2,  Yong-Hee Cho 1 2,  Sang-Kyu Lee 1 2,  JaeHeon Lee 1 2,  Woo-Jeong Jeong 1 2,  Byoung-San Moon 1 2,  Ji-Hye Yun 1 3,  Jee Sun Yang 1 2,  Sooho Choi 1 3,  Juyong Yoon 1 2,  Hyun-Yi Kim 1 2,  Mi-Yeon Kim 1 2,  Saluja Kaduwal 1 2,  Weontae Lee 1 3,  Do Sik Min 1 4,  Hoguen Kim 5,  Gyoonhee Han 1 2,  Kang-Yell Choi 1 2
Affiliations

Affiliations

  • 1 Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea.
  • 2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
  • 3 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
  • 4 Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea.
  • 5 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
PMID: 27294323 DOI: 10.1038/nchembio.2103
Abstract

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.

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