Wnt信号通路
结直肠癌
连环素
癌症研究
生物
细胞生物学
癌症
LRP6型
细胞生长
LRP5
连环蛋白
信号转导
遗传学
作者
Helen Tanton,Tomasz Sewastianik,Hyuk‐Soo Seo,David Remillard,Roodolph St. Pierre,Pratyusha Bala,Daulet Aitymbayev,Peter S. Dennis,Keith Adler,Ezekiel A. Geffken,Zoe C. Yeoh,Nicholas Vangos,Filip Garbicz,David A. Scott,Nilay S. Sethi,James E. Bradner,Sirano Dhe‐Paganon,Ruben D. Carrasco
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2022-04-29
卷期号:8 (17)
被引量:14
标识
DOI:10.1126/sciadv.abm3108
摘要
Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.
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