Discovery of an in Vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP

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• 作者：Feng Liu ; Dalia Barsyte-Lovejoy ; Fengling Li ; Yan Xiong ; Victoria Korboukh ; Xi-Ping Huang ; Abdellah Allali-Hassani ; William P. Janzen ; Bryan L. Roth ; Stephen V. Frye ; Cheryl H. Arrowsmith ; Peter J. Brown ; Masoud Vedadi ; Jian Jin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8931-8942
• 全文大小：536K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Among epigenetic 鈥渨riters鈥? 鈥渞eaders鈥? and 鈥渆rasers鈥? the lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9me2) and nonhistone proteins, have been implicated in a variety of human diseases. A 鈥渢oolkit鈥?of well-characterized chemical probes will allow biological and disease hypotheses concerning these proteins to be tested in cell-based and animal models with high confidence. We previously discovered potent and selective G9a/GLP inhibitors including the cellular chemical probe UNC0638, which displays an excellent separation of functional potency and cell toxicity. However, this inhibitor is not suitable for animal studies due to its poor pharmacokinetic (PK) properties. Here, we report the discovery of the first G9a and GLP in vivo chemical probe UNC0642, which not only maintains high in vitro and cellular potency, low cell toxicity, and excellent selectivity, but also displays improved in vivo PK properties, making it suitable for animal studies.