Target-Based Approach to Inhibitors of Histone Arginine Methyltransferases

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• 作者：Astrid Spannhoff ; Ralf Heinke ; Ingo Bauer ; Patrick Trojer ; Eric Metzger ; Ronald Gust ; Roland Schü ; le ; Gerald Brosch ; Wolfgang Sippl ; Manfred Jung
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 17, 2007
• 年：2007
• 卷：50
• 期：10
• 页码：2319 - 2325
• 全文大小：336K
• 年卷期：v.50,no.10(May 17, 2007)
• ISSN：1520-4804

文摘

Lysine and arginine methyltransferases participate in the post-translational modification of histones andregulate key cellular functions. So far only one arginine methyltransferase inhibitor discovered by randomscreening was available. We present the first target-based approach to protein arginine methyltransferase(PRMT) inhibitors. Homology models of human and Aspergillus nidulans PRMT1 were generated fromavailable X-ray structures of rat PRMTs. The NCI diversity set was filtered by a target-based virtual screeningto identify PRMT inhibitors. Employing a fungal PRMT for screening and a human enzyme for validation,we have identified seven inhibitors of PRMTs in vitro. Hit validation was achieved for two new inhibitorsby antibody mediated detection of histone hypomethylation as well as Western blotting in cancer cells.Functional activity was proven by an observed block of estrogen receptor activation. Thus, valuable chemicaltools and potential drug candidates could be identified.