title: Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
abstract: Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. Genetic knockdown of G9a inhibits cancer cell growth, and the dimethylation of p53 K373 results in the inactivation of p53. Initial SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template represented by 3a (BIX01294), a selective small molecule inhibitor of G9a and GLP, led to the discovery of 10 (UNC0224) as a potent G9a inhibitor with excellent selectivity. A high resolution X-ray crystal structure of the G9a-10 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. On the basis of the structural insights revealed by this cocrystal structure, optimization of the 7-dimethylaminopropoxy side chain of 10 resulted in the discovery of 29 (UNC0321) (Morrison K(i) = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 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: Tim J
authors.initials: TJ
authors.lastname: Wigle
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasney
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
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: Jacqueline L
authors.initials: JL
authors.lastname: Norris
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: William P
authors.initials: WP
authors.lastname: Janzen
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
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: D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D006649:Histocompatibility Antigens / Q000737:chemistry*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C551961:7-(2-(2-(dimethylamino)ethoxy)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine; D001381:Azepines; D006649:Histocompatibility Antigens; D011799:Quinazolines; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase