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

Pu Hyeon Cha, Yong Hee Cho, Sang Kyu Lee, Jaeheon Lee, Woo Jeong Jeong, Byoung San Moon, Ji Hye Yun, Jee Sun Yang, Sooho Choi, Juyong Yoon, Hyun Yi Kim, Mi Yeon Kim, Saluja Kaduwal, Weontae Lee, Do Sik Min, Hoguen Kim, Gyoonhee Han, Kang Yell Choi

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27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)593-600
Number of pages8
JournalNature Chemical Biology
Volume12
Issue number8
DOIs
Publication statusPublished - 2016 Aug 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Cha, P. H., Cho, Y. H., Lee, S. K., Lee, J., Jeong, W. J., Moon, B. S., Yun, J. H., Yang, J. S., Choi, S., Yoon, J., Kim, H. Y., Kim, M. Y., Kaduwal, S., Lee, W., Min, D. S., Kim, H., Han, G., & Choi, K. Y. (2016). Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation. Nature Chemical Biology, 12(8), 593-600. https://doi.org/10.1038/nchembio.2103