Emami Katayoon H, Nguyen Cu, Ma Hong, Kim Dae Hoon, Jeong Kwang Won, Eguchi Masakatsu, Moon Randall T, Teo Jia-Ling, Kim Hak Yeop, Moon Sung Hwan, Ha Jong Ryul, Kahn Michael
Institute for Chemical Genomics, 600 Broadway, Seattle, WA 98122, USA.
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12682-7. doi: 10.1073/pnas.0404875101. Epub 2004 Aug 16.
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.
大多数结肠癌中都会出现腺瘤性结肠息肉病基因的遗传性和体细胞突变,从而导致β-连环蛋白反应性基因的激活。为了鉴定该信号通路的小分子拮抗剂,我们用一个二级结构模板化学文库对转化的结肠直肠细胞进行筛选,寻找能够抑制β-连环蛋白反应性报告基因的化合物。我们鉴定出了ICG-001,这是一种小分子,它通过特异性结合环磷酸腺苷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。ICG-001选择性地诱导转化细胞凋亡,而不诱导正常结肠细胞凋亡,降低结肠癌细胞的体外生长能力,并且在结肠癌的Min小鼠和裸鼠异种移植模型中有效。