5yjo
Crystal structure of SmyD3 in complex with covalent inhibitor 4
Structural highlights
FunctionSMYD3_HUMAN Histone methyltransferase. Specifically methylates 'Lys-4' and 'Lys-5' of histone H3, inducing di- and tri-methylation, but not monomethylation. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences.[1] [2] Publication Abstract from PubMedSMYD3 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. Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.,Huang C, Liew SS, Lin GR, Poulsen A, Ang MJY, Chia BCS, Chew SY, Kwek ZP, Wee JLK, Ong EH, Retna P, Baburajendran N, Li R, Yu W, Koh-Stenta X, Ngo A, Manesh S, Fulwood J, Ke Z, Chung HH, Sepramaniam S, Chew XH, Dinie N, Lee MA, Chew YS, Low CB, Pendharkar V, Manoharan V, Vuddagiri S, Sangthongpitag K, Joy J, Matter A, Hill J, Keller TH, Foo K ACS Med Chem Lett. 2019 May 23;10(6):978-984. doi:, 10.1021/acsmedchemlett.9b00170. eCollection 2019 Jun 13. PMID:31223458[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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