Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Jun 22

PMID 31223458

Citations 14

Authors

Chuhui Huang

Si Si Liew

Grace R Lin

Anders Poulsen

Melgious J Y Ang

Brian C S Chia

Sin Yin Chew

Zekui P Kwek

John L K Wee

Esther H Ong

Priya Retna

Nithya Baburajendran

Rong Li

Weixuan Yu

Xiaoying Koh-Stenta

Anna Ngo

Sravanthy Manesh

Justina Fulwood

Zhiyuan Ke

Hwa Hwa Chung

Sugunavathi Sepramaniam

Xin Hui Chew

Nurul Dinie

May Ann Lee

Yun Shan Chew

Choon Bing Low

Vishal Pendharkar

Vithya Manoharan

Susmitha Vuddagiri

Kanda Sangthongpitag

Joma Joy

Alex Matter

Jeffrey Hill

Thomas H Keller

Klement Foo

Affiliations

Soon will be listed here.

Abstract

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 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.

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