C644-0303, a small-molecule inhibitor of the Wnt/β-catenin pathway, suppresses colorectal cancer growth

被引：5

作者：

Yan, Yu ^{[1
]}

Zhang, Yidan ^{[1
]}

Li, Mengyuan ^{[1
]}

Zhang, Yazhuo ^{[1
]}

Zhang, Xinxin ^{[2
]}

Zhang, Xiaonan ^{[2
]}

Xu, Yuting ^{[1
]}

Wei, Wei ^{[3
]}

Wang, Jie ^{[1
]}

Xu, Xiaohan ^{[1
]}

Song, Qiaoling ^{[1
,2
]}

Zhao, Chenyang ^{[1
,2
]}

机构：

[1] Ocean Univ China, Sch Med & Pharm, Qingdao 266071, Shandong, Peoples R China

[2] Qingdao Pilot Natl Lab Marine Sci & Technol, Innovat Platform Marine Drug Screening & Evaluat, Qingdao, Peoples R China

[3] Lanzhou Univ, Sch Life Sci, Lanzhou, Peoples R China

来源：

CANCER SCIENCE | 2021年 / 112卷 / 11期

基金：

中国国家自然科学基金;

关键词：

antitumor; colorectal cancer; high-throughput screening; small molecular inhibitor; Wnt/beta-catenin signaling; BETA-CATENIN; WNT PATHWAY; STEM-CELLS; TANKYRASE; DISCOVERY; IDENTIFICATION; CONVERGENCE; METASTASIS; ANTAGONIST; MUTATIONS;

D O I：

10.1111/cas.15118

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The Wnt/beta-catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid-enhancing factor (LEF) luciferase reporter system, the high-throughput screening of 18 840 small-molecule compounds was performed. A novel scaffold compound, C644-0303, was identified as a Wnt/beta-catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644-0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644-0303 could suppress various tumor-promoting transcription factor activities in addition to Wnt/beta-catenin. Finally, C644-0303 suppressed tumor spheroidization in a 3-dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/beta-catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.

引用

页码：4722 / 4735

页数：14

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