Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

被引：25

作者：

Huang, Chuhui ^{[1
]}

Liew, Si Si ^{[1
]}

Lin, Grace R. ^{[1
]}

Poulsen, Anders ^{[1
]}

Ang, Melgious J. Y. ^{[1
]}

Chia, Brian C. S. ^{[1
]}

Chew, Sin Yin ^{[1
]}

Kwek, Zekui P. ^{[1
]}

Wee, John L. K. ^{[1
]}

Ong, Esther H. ^{[1
]}

Retna, Priya ^{[1
]}

Baburajendran, Nithya ^{[1
]}

Li, Rong ^{[1
]}

Yu, Weixuan ^{[1
]}

Koh-Stenta, Xiaoying ^{[1
]}

Ngo, Anna ^{[1
]}

Manesh, Sravanthy ^{[1
]}

Fulwood, Justina ^{[1
]}

Ke, Zhiyuan ^{[1
]}

Chung, Hwa Hwa ^{[1
]}

Sepramaniam, Sugunavathi ^{[1
]}

Chew, Xin Hui ^{[1
]}

Dinie, Nurul ^{[1
]}

Lee, May Ann ^{[1
]}

Chew, Yun Shan ^{[1
]}

Low, Choon Bing ^{[1
]}

Pendharkar, Vishal ^{[1
]}

Manoharan, Vithya ^{[1
]}

Vuddagiri, Susmitha ^{[1
]}

Sangthongpitag, Kanda ^{[1
]}

Joy, Joma ^{[1
]}

Matter, Alex ^{[1
]}

Hill, Jeffrey ^{[1
]}

Keller, Thomas H. ^{[1
]}

Foo, Klement ^{[1
]}

机构：

[1] Expt Drug Dev Ctr, 10 Biopolis Rd 05-01 Chromos, Singapore 138670, Singapore

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 06期

关键词：

Epigenetics; Covalent; Irreversible; Methyltransferase; CELL-CULTURE; CANCER; INVASION; GROWTH; MODELS;

D O I：

10.1021/acsmedchemlett.9b00170

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

引用

页码：978 / 984

页数：13

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