A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription
A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription
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DOI：
10.1073/pnas.0404875101
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发表时间：
2004-08-24
影响因子：
11.1
通讯作者：
Kahn, M
中科院分区：
文献类型：
--
作者：
Emami, KH;Nguyen, C;Kahn, M
结肠腺瘤性息肉病的遗传和体细胞突变发生在大多数结肠癌中，导致β-连环蛋白反应基因的激活。为了鉴定该途径的小分子拮抗剂，我们用二级结构模板化的化学文库挑战转化的结直肠细胞，寻找抑制β-连环蛋白反应性报告基因的化合物。我们鉴定了ICG-001，一种通过特异性结合环AMP反应元件结合蛋白来下调β-连环蛋白/T细胞因子信号传导的小分子。ICG-001选择性地诱导转化细胞而非正常结肠细胞的凋亡，减少结肠癌细胞的体外生长，并且在结肠癌的Min小鼠和裸鼠异种移植模型中有效。
Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of beta-catenin-responsive genes. To identify small molecule antagonists of this pathway, we challenged transformed colorectal cells with a secondary structure-templated chemical library, looking for compounds that inhibit a beta-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates beta-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein. ICG-001 selectively induces apoptosis in transformed cells but not in normal colon cells, reduces in vitro growth of colon carcinoma cells, and is efficacious in the Min mouse and nude mouse xenograft models of colon cancer.