Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a

  • J Med Chem. 2009 Dec 24;52(24):7950-3. doi: 10.1021/jm901543m.
Feng Liu  1 ,  Xin Chen ,  Abdellah Allali-Hassani ,  Amy M Quinn ,  Gregory A Wasney ,  Aiping Dong ,  Dalia Barsyte ,  Ivona Kozieradzki ,  Guillermo Senisterra ,  Irene Chau ,  Alena Siarheyeva ,  Dmitri B Kireev ,  Ajit Jadhav ,  J Martin Herold ,  Stephen V Frye ,  Cheryl H Arrowsmith ,  Peter J Brown ,  Anton Simeonov ,  Masoud Vedadi ,  Jian Jin
Affiliations
  • 1. Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
PMID: 19891491 DOI: 10.1021/jm901543m
Abstract

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.

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