Structure-Activity Relationship Studies for Enhancer of Zeste Homologue 2 (EZH2) and Enhancer of Zeste Homologue 1 (EZH1) Inhibitors

被引：48

作者：

Yang, Xiaobao ^{[1
,2
]}

Li, Fengling ^{[3
]}

Konze, Kyle D. ^{[1
,2
]}

Meslamani, Jamel ^{[1
,2
]}

Ma, Anqi ^{[1
,2
]}

Brown, Peter J. ^{[3
]}

Zhou, Ming-Ming ^{[1
,2
]}

Arrowsmith, Cheryl H. ^{[3
,4
,5
]}

Kaniskan, H. Umit ^{[1
,2
]}

Vedadi, Masoud ^{[3
,6
]}

Jin, Jian ^{[1
,2
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, One Gustave L Levy Pl,Room 16-20B,Box 1677, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Dept Oncol Sci, One Gustave L Levy Pl,Room 16-20B,Box 1677, New York, NY 10029 USA

[3] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[4] Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada

[5] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada

[6] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 16期

基金：

美国国家卫生研究院; 英国惠康基金; 巴西圣保罗研究基金会; 加拿大创新基金会;

关键词：

HISTONE METHYLTRANSFERASE ACTIVITY; H3; LYSINE-27; METHYLATION; REPRESSIVE COMPLEX 2; GROUP PROTEIN EZH2; SELECTIVE-INHIBITION; BREAST-CANCER; CELL LYMPHOMA; POLYCOMB; IDENTIFICATION; PROLIFERATION;

D O I：

10.1021/acs.jmedchem.6b00855

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on Modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity.

引用

页码：7617 / 7633

页数：17

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