Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation
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 mos...
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Published in | Nature chemical biology Vol. 12; no. 8; pp. 593 - 600 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.08.2016
|
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1552-4450 1552-4469 |
DOI: | 10.1038/nchembio.2103 |