A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol 2011 Jul 10;7(8):566-74
Date
07/12/2011Pubmed ID
21743462Pubmed Central ID
PMC3184254DOI
10.1038/nchembio.599Scopus ID
2-s2.0-79960493567 (requires institutional sign-in at Scopus site) 419 CitationsAbstract
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
Author List
Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Wang SC, Chen X, Chau I, Mangano TJ, Huang XP, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Petronis A, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin JAuthor
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Line
Enzyme Inhibitors
Gene Silencing
Histone-Lysine N-Methyltransferase
Humans
Mice
Molecular Structure
Quinazolines