- Protein lysine methyltransferase g9a inhibitors: Design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines.
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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 Ki = 63 pM), which is the first G9a inhibitor with picomolar potency and the most potent G9a inhibitor to date.
- Liu, Feng,Chen, Xin,Allali-Hassani, Abdellah,Quinn, Amy M.,Wigle, Tim J.,Wasney, Gregory A.,Dong, Aiping,Senisterra, Guillermo,Chau, Irene,Siarheyeva, Alena,Norris, Jacqueline L.,Kireev, Dmitri B.,Jadhav, Ajit,Herold, J. Martin,Janzen, William P.,Arrowsmith, Cheryl H.,Frye, Stephen V.,Brown, Peter J.,Simeonov, Anton,Vedadi, Masoud,Jin, Jian
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experimental part
p. 5844 - 5857
(2010/10/03)
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- Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a
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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,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
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supporting information; experimental part
p. 7950 - 7953
(2010/08/13)
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