Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
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.
Liu
Feng
F
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.
Chen
Xin
X
Allali-Hassani
Abdellah
A
Quinn
Amy M
AM
Wigle
Tim J
TJ
Wasney
Gregory A
GA
Dong
Aiping
A
Senisterra
Guillermo
G
Chau
Irene
I
Siarheyeva
Alena
A
Norris
Jacqueline L
JL
Kireev
Dmitri B
DB
Jadhav
Ajit
A
Herold
J Martin
JM
Janzen
William P
WP
Arrowsmith
Cheryl H
CH
Frye
Stephen V
SV
Brown
Peter J
PJ
Simeonov
Anton
A
Vedadi
Masoud
M
Jin
Jian
J
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
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