Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation

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Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 5′-terminal mRNA cap structure (m 7 GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design cap-binding inhibitors of eIF4E by modifying the N 7 -substituent of m 7 GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N -[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5- g ]quinolin-7-yl)methyl]- N ′-(2-methyl-propyl)- N -(phenyl-methyl)thiourea ( 14 ), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m 7 GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 5′-deoxy - 5′-(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino- N 7 -methyl-guanosine ( 4a ), N 7 -3-chlorobenzyl-5′-deoxy - 5′-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine ( 4f ), and N 7 -benzyl-5′-deoxy - 5′-(trifluoromethyl-sulfamoyl)guanosine ( 7a ). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.