Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3.

Autor:	Huang C; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Liew SS; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Lin GR; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Poulsen A; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Ang MJY; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Chia BCS; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Chew SY; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Kwek ZP; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Wee JLK; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Ong EH; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Retna P; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Baburajendran N; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Li R; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Yu W; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Koh-Stenta X; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Ngo A; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Manesh S; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Fulwood J; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Ke Z; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Chung HH; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Sepramaniam S; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Chew XH; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Dinie N; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Lee MA; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Chew YS; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Low CB; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Pendharkar V; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Manoharan V; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Vuddagiri S; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Sangthongpitag K; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Joy J; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Matter A; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Hill J; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Keller TH; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670., Foo K; Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, Singapore 138670.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2019 May 23; Vol. 10 (6), pp. 978-984. Date of Electronic Publication: 2019 May 23 (Print Publication: 2019).
DOI:	10.1021/acsmedchemlett.9b00170
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest.
Databáze:	MEDLINE
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