Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

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, and Klement Foo

ACS Medicinal Chemistry Letters, 2019
DOI: 10.1021/acsmedchemlett.9b00170

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.