Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy-quinazolines.

被引：169

作者：

Liu, Feng ^{[1
]}

Chen, Xin ^{[1
]}

Allali-Hassani, Abdellah ^{[2
]}

Quinn, Amy M. ^{[3
]}

Wigle, Tim J. ^{[1
]}

Wasney, Gregory A. ^{[2
]}

Dong, Aiping ^{[2
]}

Senisterra, Guillermo ^{[2
]}

Chau, Irene ^{[2
]}

Siarheyeva, Alena ^{[2
]}

Norris, Jacqueline L. ^{[1
]}

Kireev, Dmitri B. ^{[1
]}

Jadhav, Ajit ^{[3
]}

Herold, J. Martin ^{[1
]}

Janzen, William P. ^{[1
]}

Arrowsmith, Cheryl H. ^{[2
]}

Frye, Stephen V. ^{[1
]}

Brown, Peter J. ^{[2
]}

Simeonov, Anton ^{[3
]}

Vedadi, Masoud ^{[2
]}

Jin, Jian ^{[1
]}

机构：

[1] Univ N Carolina, Ctr Integrat 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 1L7, Canada

[3] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 15期

基金：

加拿大创新基金会; 英国惠康基金;

关键词：

PLURIPOTENT STEM-CELLS; HISTONE METHYLTRANSFERASE; CHROMATIN-STRUCTURE; CANCER; METHYLATION; STABILITY; GENES;

D O I：

10.1021/jm100478y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison K(i) = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.

引用

页码：5844 / 5857

页数：14

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