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Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.

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 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.

SUBMITTER: Huang C 

PROVIDER: S-EPMC6580565 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.

Huang Chuhui C   Liew Si Si SS   Lin Grace R GR   Poulsen Anders A   Ang Melgious J Y MJY   Chia Brian C S BCS   Chew Sin Yin SY   Kwek Zekui P ZP   Wee John L K JLK   Ong Esther H EH   Retna Priya P   Baburajendran Nithya N   Li Rong R   Yu Weixuan W   Koh-Stenta Xiaoying X   Ngo Anna A   Manesh Sravanthy S   Fulwood Justina J   Ke Zhiyuan Z   Chung Hwa Hwa HH   Sepramaniam Sugunavathi S   Chew Xin Hui XH   Dinie Nurul N   Lee May Ann MA   Chew Yun Shan YS   Low Choon Bing CB   Pendharkar Vishal V   Manoharan Vithya V   Vuddagiri Susmitha S   Sangthongpitag Kanda K   Joy Joma J   Matter Alex A   Hill Jeffrey J   Keller Thomas H TH   Foo Klement K  

ACS medicinal chemistry letters 20190523 6

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 <b>29</b> exhibits high potency by inhibiting SMYD3's enzymatic activity and showing antiproliferat  ...[more]

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