Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a

被引：187

作者：

Liu, Feng ^{[1
]}

Chen, Xin ^{[1
]}

Allali-Hassani, Abdellah ^{[2
]}

Quinn, Amy M. ^{[3
]}

Wasney, Gregory A. ^{[2
]}

Dong, Aiping ^{[2
]}

Barsyte, Dalia ^{[2
]}

Kozieradzki, Ivona ^{[2
]}

Senisterra, Guillermo ^{[2
]}

Chau, Irene ^{[2
]}

Siarheyeva, Alena ^{[2
]}

Kireev, Dmitri B. ^{[1
]}

Jadhav, Ajit ^{[3
]}

Herold, J. Martin ^{[1
]}

Frye, Stephen V. ^{[1
]}

Arrowsmith, Cheryl H. ^{[2
]}

Brown, Peter J. ^{[2
]}

Simeonov, Anton ^{[3
]}

Vedadi, Masoud ^{[2
]}

Jin, Jian ^{[1
]}

机构：

[1] Univ N Carolina, Ctr Integrated Chem Biol & Drug Discovery, Div Med Chem & Nat Prod, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

[2] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L6, Canada

[3] Natl Human Genome Res Inst, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 24期

关键词：

CHROMATIN-STRUCTURE; CANCER;

D O I：

10.1021/jm901543m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as it potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.

引用

页码：7950 / 7953

页数：4

共 20 条

[1] The mammalian epigenome [J].

Bernstein, Bradley E. ;

Meissner, Alexander ;

Lander, Eric S. .

CELL, 2007, 128 (04) :669-681

[2] Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294 [J].

Chang, Yanqi ;

Zhang, Xing ;

Horton, John R. ;

Upadhyay, Anup K. ;

Spannhoff, Astrid ;

Liu, Jin ;

Snyder, James P. ;

Bedford, Mark T. ;

Cheng, Xiaodong .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2009, 16 (03) :312-317

[3] Chemical probes for histone-modifying enzymes [J].

Cole, Philip A. .

NATURE CHEMICAL BIOLOGY, 2008, 4 (10) :590-597

[4] A coupled fluorescent assay for histone methyltransferases [J].

Collazo, E ;

Couture, JF ;

Bulfer, S ;

Trievel, RC .

ANALYTICAL BIOCHEMISTRY, 2005, 342 (01) :86-92

[5] Molecular origins of cancer: Epigenetics in cancer [J].

Esteller, Manel .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (11) :1148-1159

[6] Chromatin-modifying proteins in cancer [J].

Fog, Cathrine K. ;

Jensen, Klaus T. ;

Lund, Anders H. .

APMIS, 2007, 115 (10) :1060-1089

[7] Role of histone modifications in defining chromatin structure and function [J].

Gelato, Kathy A. ;

Fischle, Wolfgang .

BIOLOGICAL CHEMISTRY, 2008, 389 (04) :353-363

[8] Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9 [J].

Greiner, D ;

Bonaldi, T ;

Eskeland, R ;

Roemer, E ;

Imhof, A .

NATURE CHEMICAL BIOLOGY, 2005, 1 (03) :143-145

[9] Translating the histone code [J].

Jenuwein, T ;

Allis, CD .

SCIENCE, 2001, 293 (5532) :1074-1080

[10]

KONDO Y, 2008, PLOS ONE, V3

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