title: Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a.
abstract: SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Amy M
authors.initials: AM
authors.lastname: Quinn
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasney
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.forename: Irene
authors.initials: I
authors.lastname: Chau
authors.forename: Alena
authors.initials: A
authors.lastname: Siarheyeva
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kireev
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: J Martin
authors.initials: JM
authors.lastname: Herold
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D011495:Histone-Lysine N-Methyltransferase