title: Structure-guided design, synthesis, and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interaction.
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.
authors.affiliation: Department of Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA. xiaoqic@amgen.com
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Chen
authors.forename: David J
authors.initials: DJ
authors.lastname: Kopecky
authors.forename: Jeff
authors.initials: J
authors.lastname: Mihalic
authors.forename: Shawn
authors.initials: S
authors.lastname: Jeffries
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Min
authors.forename: Julie
authors.initials: J
authors.lastname: Heath
authors.forename: Jeff
authors.initials: J
authors.lastname: Deignan
authors.forename: Sujen
authors.initials: S
authors.lastname: Lai
authors.forename: Zice
authors.initials: Z
authors.lastname: Fu
authors.forename: Cristiano
authors.initials: C
authors.lastname: Guimaraes
authors.forename: Shanling
authors.initials: S
authors.lastname: Shen
authors.forename: Shyun
authors.initials: S
authors.lastname: Li
authors.forename: Sheree
authors.initials: S
authors.lastname: Johnstone
authors.forename: Stephen
authors.initials: S
authors.lastname: Thibault
authors.forename: Haoda
authors.initials: H
authors.lastname: Xu
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.forename: Nigel
authors.initials: N
authors.lastname: Walker
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D010757:Phosphorous Acids; D014176:Protein Biosynthesis / Q000187:drug effects; D012315:RNA Caps / Q000737:chemistry / Q000378:metabolism*; D011817:Rabbits; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C573558:4-(7-(2-(4-chlorophenoxy)ethyl)-6-hydroxy-2-(methylamino)-7H-purin-8-yl)phenylphosphonic acid; D039561:Eukaryotic Initiation Factor-4E; D063065:Organophosphonates; D010757:Phosphorous Acids; D012315:RNA Caps; D006147:Guanine; D006157:Guanosine Monophosphate