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

• Published in: Journal of medicinal chemistry Vol. 55; no. 8; pp. 3837 - 3851
• Main Authors: Chen, Xiaoqi, Kopecky, David J, Mihalic, Jeff, Jeffries, Shawn, Min, Xiaoshan, Heath, Julie, Deignan, Jeff, Lai, SuJen, Fu, Zice, Guimaraes, Cristiano, Shen, Shanling, Li, Shyun, Johnstone, Sheree, Thibault, Stephen, Xu, Haoda, Cardozo, Mario, Shen, Wang, Walker, Nigel, Kayser, Frank, Wang, Zhulun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.04.2012; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Crystallography, X-Ray; Drug Design; Eukaryotic Initiation Factor-4E - chemistry; Eukaryotic Initiation Factor-4E - metabolism; Guanine - analogs & derivatives; Guanine - chemical synthesis; Guanine - pharmacology; Guanosine Monophosphate - analogs & derivatives; Guanosine Monophosphate - chemical synthesis; Guanosine Monophosphate - pharmacology; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Models, Molecular; Organophosphonates - chemical synthesis; Organophosphonates - pharmacology; Pharmacology & Pharmacy; Phosphorous Acids; Protein Biosynthesis - drug effects; Rabbits; Reticulocytes - drug effects; Reticulocytes - metabolism; RNA Caps - chemistry; RNA Caps - metabolism; Science & Technology; Structure-Activity Relationship; TRANSPORT; CYCLIN D1; ANALOGS; DEPENDENT TRANSLATION; FACTOR 4E; INITIATION-FACTOR EIF4E; TRANSLATION INITIATION; EUKARYOTIC TRANSLATION; BINDING PROTEIN; EXPRESSION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300037x

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 IC50 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.