Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a

• Published in: Journal of medicinal chemistry 2009-12, Vol.52 (24), p.7950-7953
• Main Authors: Liu, Feng, Chen, Xin, Allali-Hassani, Abdellah, Quinn, Amy M, Wasney, Gregory A, Dong, Aiping, Barsyte, Dalia, Kozieradzki, Ivona, Senisterra, Guillermo, Chau, Irene, Siarheyeva, Alena, Kireev, Dmitri B, Jadhav, Ajit, Herold, J. Martin, Frye, Stephen V, Arrowsmith, Cheryl H, Brown, Peter J, Simeonov, Anton, Vedadi, Masoud, Jin, Jian
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Histone-Lysine N-Methyltransferase - antagonists & inhibitors; Histone-Lysine N-Methyltransferase - chemistry; Histone-Lysine N-Methyltransferase - metabolism; Medical sciences; Miscellaneous; Models, Molecular; Pharmacology. Drug treatments; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Structure-Activity Relationship; Transferases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm901543m

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.