Structure-Guided Design, Synthesis, and Evaluation of Guanine-Derived Inhibitors of the eIF4E mRNA鈥揅ap Interaction

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• 作者：Xiaoqi Chen ; David J. Kopecky ; Jeff Mihalic ; Shawn Jeffries ; Xiaoshan Min ; Julie Heath ; Jeff Deignan ; SuJen Lai ; Zice Fu ; Cristiano Guimaraes ; Shanling Shen ; Shyun Li ; Sheree Johnstone ; Stephen Thibault ; Haoda Xu ; Mario Cardozo ; Wang Shen ; Nigel Walker ; Frank Kayser ; Zhulun Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3837-3851
• 全文大小：560K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5鈥?terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC₅₀ of 2.5 渭M for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.