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

• DOI: 10.1016/j.ejmech.2016.08.047
• Publication Date: 2016-08-25T21:27:51Z
• Authors: Fadi Soukarieh; Matthew W. Nowicki; Amandine Bastide; Tuija Pöyry; Carolyn Jones; Kate Dudek; Geetanjali Patwar...; François Meullenet; Neil J. Oldham; Malcolm D. Walkin...; Anne E. Willis; Peter M. Fischer
• Keywords: Models, Molecular; RNA Caps; 0301 basic medicine; mRNA translation; protein synthesis; Protein Conformation; Chemistry Techniques, Synthetic; 03 medical and health sciences; Biomimetic Materials; Drug Discovery; cancer; Animals; Cancer; Pharmacology; Nucleotides; Organic Chemistry; Thiourea; 500; 540; Eukaryotic Initiation Factor-4E; Cap-binding inhibitor; eIF4E; Drug Design; Rabbits; Protein synthesis; cap-binding inhibitor; Research Paper

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 (m7GpppN, 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 N7-substituent of m7GMP 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 m7GMP 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-N7-methyl-guanosine (4a), N7-3-chlorobenzyl-5'-deoxy-5'-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7-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.