title: A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells.
abstract: 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.
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors: Masoud
authors: M
authors: Vedadi
authors: Dalia
authors: D
authors: Barsyte-Lovejoy
authors: Feng
authors: F
authors: Liu
authors: Sylvie
authors: S
authors: Rival-Gervier
authors: Abdellah
authors: A
authors: Allali-Hassani
authors: Viviane
authors: V
authors: Labrie
authors: Tim J
authors: TJ
authors: Wigle
authors: Peter A
authors: PA
authors: Dimaggio
authors: Gregory A
authors: GA
authors: Wasney
authors: Alena
authors: A
authors: Siarheyeva
authors: Aiping
authors: A
authors: Dong
authors: Wolfram
authors: W
authors: Tempel
authors: Sun-Chong
authors: SC
authors: Wang
authors: Xin
authors: X
authors: Chen
authors: Irene
authors: I
authors: Chau
authors: Thomas J
authors: TJ
authors: Mangano
authors: Xi-Ping
authors: XP
authors: Huang
authors: Catherine D
authors: CD
authors: Simpson
authors: Samantha G
authors: SG
authors: Pattenden
authors: Jacqueline L
authors: JL
authors: Norris
authors: Dmitri B
authors: DB
authors: Kireev
authors: Ashutosh
authors: A
authors: Tripathy
authors: Aled
authors: A
authors: Edwards
authors: Bryan L
authors: BL
authors: Roth
authors: William P
authors: WP
authors: Janzen
authors: Benjamin A
authors: BA
authors: Garcia
authors: Arturas
authors: A
authors: Petronis
authors: James
authors: J
authors: Ellis
authors: Peter J
authors: PJ
authors: Brown
authors: Stephen V
authors: SV
authors: Frye
authors: Cheryl H
authors: CH
authors: Arrowsmith
authors: Jian
authors: J
authors: Jin
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; C561310:UNC 0638; C533711:G9a protein, mouse; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase