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

Authors
 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 
Citation
 NATURE CHEMICAL BIOLOGY, Vol.12(8) : 593-600, 2016 
Journal Title
 NATURE CHEMICAL BIOLOGY 
ISSN
 1552-4450 
Issue Date
2016
MeSH
Animals ; Axin Protein/chemistry* ; Axin Protein/metabolism* ; Binding Sites ; Cell Proliferation/drug effects ; 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 ; beta Catenin/chemistry ; beta Catenin/metabolism*
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.
Full Text
http://www.nature.com/nchembio/journal/v12/n8/full/nchembio.2103.html
DOI
10.1038/nchembio.2103
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hogeun(김호근)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/147223
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