Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

被引：24

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

共 50 条

[1] Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3 (vol 6, pg 978, 2019)
Huang, Chuhui
Liew, Si Si
Lin, Grace R.
Poulsen, Anders
Ang, Melgious J. Y.
Chia, Brian C. S.
Chew, Sin Yin
Kwek, Zekui P.
Wee, John L. K.
Ong, Esther H.
Retna, Priya
Baburajendran, Nithya
Li, Rong
Yu, Weixuan
Koh-Stenta, Xiaoying
Ngo, Anna
Manesh, Sravanthy
Fulwood, Justina
Ke, Zhiyuan
Chung, Hwa Hwa
Sepramaniam, Sugunavathi
Chew, Xin Hui
Dinie, Nurul
Lee, May Ann
Chew, Yun Shan
Low, Choon Bing
Pendharkar, Vishal
Manoharan, Vithya
Vuddagiri, Susmitha
Sangthongpitag, Kanda
Joy, Joma
Matter, Alex
Hill, Jeffrey
Keller, Thomas H.
Foo, Klement
ACS MEDICINAL CHEMISTRY LETTERS, 2019, 10 (08): : 1240 - 1240
[2] Structure-base targeting of SMYD3: An histone methyltransferase involved in colorectal tumorigenesis
Barbosa, Armenio Jorge M.
Peserico, Alessia
Simone, Cristiano
Del Rio, Alberto
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2013, 245
[3] Structural and Functional Profiling of the Human Histone Methyltransferase SMYD3
Foreman, Kenneth W.
Brown, Mark
Park, Frances
Emtage, Spencer
Harriss, June
Das, Chhaya
Zhu, Li
Crew, Andy
Arnold, Lee
Shaaban, Salam
Tucker, Philip
PLOS ONE, 2011, 6 (07):
[4] Histone methyltransferase Smyd3 is a new regulator for vascular senescence
Yang, Di
Wei, Gang
Long, Fen
Nie, Hongbo
Tian, Xiaoli
Qu, Lefeng
Wang, ShuangXi
Li, Peng
Qiu, Yue
Wang, Yang
Hong, Wanjin
Ni, Ting
Liu, Xinhua
Zhu, Yi Zhun
AGING CELL, 2020, 19 (09)
[5] Role of the SMYD3 histone methyltransferase in tumorigenesis Local or global effects?
Medjkane, Souhila
Cock-Rada, Alicia
Weitzman, Jonathan B.
CELL CYCLE, 2012, 11 (10) : 1865 - 1865
[6] SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells
Hamamoto, R
Furukawa, Y
Morita, M
Iimura, Y
Silva, FP
Li, MH
Yagyu, R
Nakamura, Y
NATURE CELL BIOLOGY, 2004, 6 (08) : 731 - 740
[7] SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells
Ryuji Hamamoto
Yoichi Furukawa
Masashi Morita
Yuko Iimura
Fabio Pittella Silva
Meihua Li
Ryuichiro Yagyu
Yusuke Nakamura
Nature Cell Biology, 2004, 6 : 731 - 740
[8] Structural Insights into the Autoinhibition and Posttranslational Activation of Histone Methyltransferase SmyD3
Sirinupong, Nualpun
Brunzelle, Joseph
Doko, Ernada
Yang, Zhe
JOURNAL OF MOLECULAR BIOLOGY, 2011, 406 (01) : 149 - 159
[9] Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase
Talibov, Vladimir O.
Fabini, Edoardo
FitzGerald, Edward A.
Tedesco, Daniele
Cederfeldt, Daniela
Talu, Martin J.
Rachman, Moira M.
Mihalic, Filip
Manoni, Elisabetta
Naldi, Marina
Sanese, Paola
Forte, Giovanna
Signorile, Martina Lepore
Barril, Xavier
Simone, Cristiano
Bartolini, Manuela
Dobritzsch, Doreen
Del Rio, Alberto
Danielson, U. Helena
CHEMBIOCHEM, 2021, 22 (09) : 1597 - 1608
[10] Histone methyltransferase Smyd3 regulates early embryonic lineage commitment in mice
Suzuki, Shinnosuke
Nozawa, Yusuke
Tsukamoto, Satoshi
Kaneko, Takehito
Imai, Hiroshi
Minami, Naojiro
REPRODUCTION, 2015, 150 (01) : 21 - 30

← 1 2 3 4 5 →