2. Academic Validation
  3. Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

  • ACS Med Chem Lett. 2019 May 23;10(6):978-984. doi: 10.1021/acsmedchemlett.9b00170.
Chuhui Huang 1,  Si Si Liew 1,  Grace R Lin 1,  Anders Poulsen 1,  Melgious J Y Ang 1,  Brian C S Chia 1,  Sin Yin Chew 1,  Zekui P Kwek 1,  John L K Wee 1,  Esther H Ong 1,  Priya Retna 1,  Nithya Baburajendran 1,  Rong Li 1,  Weixuan Yu 1,  Xiaoying Koh-Stenta 1,  Anna Ngo 1,  Sravanthy Manesh 1,  Justina Fulwood 1,  Zhiyuan Ke 1,  Hwa Hwa Chung 1,  Sugunavathi Sepramaniam 1,  Xin Hui Chew 1,  Nurul Dinie 1,  May Ann Lee 1,  Yun Shan Chew 1,  Choon Bing Low 1,  Vishal Pendharkar 1,  Vithya Manoharan 1,  Susmitha Vuddagiri 1,  Kanda Sangthongpitag 1,  Joma Joy 1,  Alex Matter 1,  Jeffrey Hill 1,  Thomas H Keller 1,  Klement Foo 1
Affiliations

Affiliation

  • 1 Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670.
PMID: 31223458 DOI: 10.1021/acsmedchemlett.9b00170
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.

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