Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a.
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.
Liu
Feng
F
Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Chen
Xin
X
Allali-Hassani
Abdellah
A
Quinn
Amy M
AM
Wasney
Gregory A
GA
Dong
Aiping
A
Barsyte
Dalia
D
Kozieradzki
Ivona
I
Senisterra
Guillermo
G
Chau
Irene
I
Siarheyeva
Alena
A
Kireev
Dmitri B
DB
Jadhav
Ajit
A
Herold
J Martin
JM
Frye
Stephen V
SV
Arrowsmith
Cheryl H
CH
Brown
Peter J
PJ
Simeonov
Anton
A
Vedadi
Masoud
M
Jin
Jian
J
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
D004791:Enzyme Inhibitors; D011799:Quinazolines; D011495:Histone-Lysine N-Methyltransferase