ICG-001, A Novel Small Molecule Regulator of TCF/β-Catenin Transcription

被引：98

作者：

Eguchi, Masakatsu ^{[1
]}

Cu Nguyen ^{[1
]}

Lee, Sung Chan ^{[1
]}

Kahn, Michael ^{[1
,2
]}

机构：

[1] Inst Chem Genom, Seattle, WA 98122 USA

[2] Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA

来源：

MEDICINAL CHEMISTRY | 2005年 / 1卷 / 05期

关键词：

Peptidomimetics; Anti-cancer; Wnt Pathway; beta-Catenin;

D O I：

10.2174/1573406054864098

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inherited and somatic mutations in the APC gene, a human tumor-suppressor, occur in a large percentage of colon cancers, leading to elevated levels of nuclear beta-Catenin, and to activation of TCF/beta-Catenin-responsive genes including cyclin D1 and c-myc. To identify small molecule antagonists of this pathway, we screened transformed colorectal cells with a secondary structure-templated chemical library, in search of compounds that attenuated a TCF/beta-Catenin-responsive reporter gene. From this library we selected ICG-001 (IC50 = 3 mu M) as a lead compound. Design and synthesis of the chemical library and some preliminary biological evaluation is described.

引用

页码：467 / 472

页数：6

共 22 条

[11] Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC(-/-) colon carcinoma [J].

Korinek, V ;

Barker, N ;

Morin, PJ ;

vanWichen, D ;

deWeger, R ;

Kinzler, KW ;

Vogelstein, B ;

Clevers, H .

SCIENCE, 1997, 275 (5307) :1784-1787

[12] The promise and perils of Wnt signaling through β-catenin [J].

Moon, RT ;

Bowerman, B ;

Boutros, M ;

Perrimon, N .

SCIENCE, 2002, 296 (5573) :1644-1646

[13] WNT and β-catenin signalling:: Diseases and therapies [J].

Moon, RT ;

Kohn, AD ;

De Ferrari, GV ;

Kaykas, A .

NATURE REVIEWS GENETICS, 2004, 5 (09) :689-699

[14]

Morin PJ, 1999, BIOESSAYS, V21, P1021, DOI 10.1002/(SICI)1521-1878(199912)22:1<1021::AID-BIES6>3.0.CO

[15]

2-P

[16] Molecular causes of colon cancer [J].

Oving, IM ;

Clevers, HC .

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 2002, 32 (06) :448-457

[17] The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway [J].

Shtutman, M ;

Zhurinsky, J ;

Simcha, I ;

Albanese, C ;

D'Amico, M ;

Pestell, R ;

Ben-Ze'ev, A .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (10) :5522-5527

[18] The transcriptional coactivator CBP interacts with β-catenin to activate gene expression [J].

Takemaru, KI ;

Moon, RT .

JOURNAL OF CELL BIOLOGY, 2000, 149 (02) :249-254

[19] β-catenin regulates expression of cyclin D1 in colon carcinoma cells [J].

Tetsu, O ;

McCormick, F .

NATURE, 1999, 398 (6726) :422-426

[20] Analysis of human transcriptomes [J].

Velculescu, VE ;

Madden, SL ;

Zhang, L ;

Lash, AE ;

Yu, J ;

Rago, C ;

Lal, A ;

Wang, CJ ;

Beaudry, GA ;

Ciriello, KM ;

Cook, BP ;

Dufault, MR ;

Ferguson, AT ;

Gao, YH ;

He, TC ;

Hermeking, H ;

Hiraldo, SK ;

Hwang, PM ;

Lopez, MA ;

Luderer, HF ;

Mathews, B ;

Petroziello, JM ;

Polyak, K ;

Zawel, L ;

Zhang, W ;

Zhang, XM ;

Zhou, W ;

Haluska, FG ;

Jen, J ;

Sukumar, S ;

Landes, GM ;

Riggins, GJ ;

Vogelstein, B ;

Kinzler, KW .

NATURE GENETICS, 1999, 23 (04) :387-388

← 1 2 3 →