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: Feng Liu, Xin Chen, Abdellah Allali-Hassani, Amy M Quinn, Tim J Wigle, Gregory A Wasney, Aiping Dong, Guillermo Senisterra, Irene Chau, Alena Siarheyeva, Jacqueline L Norris, Dmitri B Kireev, Ajit Jadhav, J Martin Herold, William P Janzen, Cheryl H Arrowsmith, Stephen V Frye, Peter J Brown, Anton Simeonov, Masoud Vedadi, Jian Jin
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 15 Pg. 5844-57 (Aug 12 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20614940 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 7-(2-(2-(dimethylamino)ethoxy)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine
• Azepines
• Histocompatibility Antigens
• Quinazolines
• EHMT2 protein, human
• Histone-Lysine N-Methyltransferase

Topics

• Azepines (chemical synthesis, chemistry)
• Crystallography, X-Ray
• Drug Design
• Histocompatibility Antigens (chemistry)
• Histone-Lysine N-Methyltransferase (antagonists & inhibitors, chemistry)
• Humans
• Models, Molecular
• Protein Binding
• Protein Conformation
• Quinazolines (chemical synthesis, chemistry)
• Structure-Activity Relationship