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

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.

SUBMITTER: Liu F

PROVIDER: S-EPMC2825141 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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

Liu Feng F Chen Xin X Allali-Hassani Abdellah A Quinn Amy M AM Wasney Gregory A GA Dong Aiping A Barsyte Dalia D Kozieradzki Ivona I Senisterra Guillermo G Chau Irene I Siarheyeva Alena A Kireev Dmitri B DB Jadhav Ajit A Herold J Martin JM Frye Stephen V SV Arrowsmith Cheryl H CH Brown Peter J PJ Simeonov Anton A Vedadi Masoud M Jin Jian J

Journal of medicinal chemistry 20091201 24

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 remode ...[more]

PMID: 19891491

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