Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex

被引:584
作者
Lepourcelet, M
Chen, YNP
France, DS
Wang, HS
Crews, P
Petersen, F
Bruseo, C
Wood, AW
Shivdasani, RA
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[2] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[3] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[5] Novartis Inst Biomed Res, Dept Oncol, Cambridge, MA 02139 USA
[6] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA
[7] Univ Calif Santa Cruz, Inst Marine Sci, Santa Cruz, CA 95064 USA
关键词
D O I
10.1016/S1535-6108(03)00334-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Key molecular lesions in colorectal and other cancers cause beta-catenin-dependent transactivation of T cell factor (Tcf)dependent genes. Disruption of this signal represents an opportunity for rational cancer therapy. To identify compounds that inhibit association between Tcf4 and beta-catenin, we screened libraries of natural compounds in a high-throughput assay for immunoenzymatic detection of the protein-protein interaction. Selected compounds disrupt Tcf/beta-catenin complexes in several independent in vitro assays and potently antagonize cellular effects of beta-catenin-dependent activities, including reporter gene activation, c-myc or cyclin D1 expression, cell proliferation, and duplication of the Xenopus embryonic dorsal axis. These compounds thus meet predicted criteria for disrupting Tcf/beta-catenin complexes and define a general standard to establish mechanism-based activity of small molecule inhibitors of this pathogenic protein-protein interaction.
引用
收藏
页码:91 / 102
页数:12
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