Abstract
The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' 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 IC(50) of 2.5 μM 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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Crystallography, X-Ray
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Drug Design
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Eukaryotic Initiation Factor-4E / chemistry
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Eukaryotic Initiation Factor-4E / metabolism*
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Guanine / analogs & derivatives*
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Guanine / chemical synthesis
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Guanine / pharmacology
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Guanosine Monophosphate / analogs & derivatives*
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Guanosine Monophosphate / chemical synthesis
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Guanosine Monophosphate / pharmacology*
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Humans
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Inhibitory Concentration 50
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Models, Molecular
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Organophosphonates / chemical synthesis*
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Organophosphonates / pharmacology
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Phosphorous Acids
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Protein Biosynthesis / drug effects
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RNA Caps / chemistry
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RNA Caps / metabolism*
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Rabbits
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Reticulocytes / drug effects
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Reticulocytes / metabolism
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Structure-Activity Relationship
Substances
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4-(7-(2-(4-chlorophenoxy)ethyl)-6-hydroxy-2-(methylamino)-7H-purin-8-yl)phenylphosphonic acid
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Eukaryotic Initiation Factor-4E
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Organophosphonates
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Phosphorous Acids
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RNA Caps
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Guanine
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Guanosine Monophosphate