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

[31] Exploration of the Substrate Preference of Lysine Methyltransferase SMYD3 by Molecular Dynamics Simulations
Sun, Jixue
Shi, Fandi
Yang, Na
ACS OMEGA, 2019, 4 (22): : 19573 - 19581
[32] Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via HMGA2 transcription
Gu, Wenchao
Yang, Zongcheng
Nakajima, Takahito
CANCER SCIENCE, 2024, 115 : 782 - 782
[33] Discovery of a novel potent selective SMYD3 inhibitor with oral bioavailability
Mitchell, Lorna
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2016, 251
[34] Upregulation of SMYD3 and SMYD3 VNTR 3/3 polymorphism increase the risk of hepatocellular carcinoma
Mai Thanh Binh
Nghiem Xuan Hoan
Dao Phuong Giang
Hoang Van Tong
Bock, C-Thomas
Wedemeyer, Heiner
Nguyen Linh Toan
Mai Hong Bang
Kremsner, Peter G.
Meyer, Christian G.
Le Huu Song
Velavan, Thirumalaisamy P.
SCIENTIFIC REPORTS, 2020, 10 (01)
[35] Upregulation of SMYD3 and SMYD3 VNTR 3/3 polymorphism increase the risk of hepatocellular carcinoma
Mai Thanh Binh
Nghiem Xuan Hoan
Dao Phuong Giang
Hoang Van Tong
C.-Thomas Bock
Heiner Wedemeyer
Nguyen Linh Toan
Mai Hong Bang
Peter G. Kremsner
Christian G. Meyer
Le Huu Song
Thirumalaisamy P. Velavan
Scientific Reports, 10
[36] Conformational Dynamics of Lysine Methyltransferase Smyd2. Insights into the Different Substrate Crevice Characteristics of Smyd2 and Smyd3
Chandramouli, Balasubramanian
Chillemi, Giovanni
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2016, 56 (12) : 2467 - 2475
[37] Genotype analysis of the VNTR polymorphism in the SMYD3 histone methyltransferase gene:: Lack of correlation with the level of histone H3 methylation in NSCLC tissues or with the risk of NSCLC
Barlesi, Fabrice
Giaccone, Giuseppe
Gallegos-Ruiz, Marielle I.
Span, Simone W.
Lefesvre, Pierre
Kruyt, Frank A. E.
Rodriguez, Jose Antonio
INTERNATIONAL JOURNAL OF CANCER, 2008, 122 (06) : 1441 - 1442
[38] SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways
Bottino, Cinzia
Peserico, Alessia
Simone, Cristiano
Caretti, Giuseppina
CANCERS, 2020, 12 (01)
[39] Mutated KRAS Results in Overexpression of DUSP4, a MAP-Kinase Phosphatase, and SMYD3, a Histone Methyltransferase, in Rectal Carcinomas
Gaedcke, Jochen
Grade, Marian
Jung, Klaus
Camps, Jordi
Jo, Peter
Emons, Georg
Gehoff, Anastasia
Sax, Ulrich
Schirmer, Markus
Becker, Heinz
Beissbarth, Tim
Ried, Thomas
Ghadimi, B. Michael
GENES CHROMOSOMES & CANCER, 2010, 49 (11): : 1024 - 1034
[40] Cell geometry and the cytoskeleton impact the nucleo-cytoplasmic localisation of the SMYD3 methyltransferase
Pereira, David
Richert, Alain
Medjkane, Souhila
Henon, Sylvie
Weitzman, Jonathan B.
SCIENTIFIC REPORTS, 2020, 10 (01)

← 1 2 3 4 5 →