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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 DOI Help

Authors: Fadi Soukarieh (School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham) , Matthew Nowicki (University of Edinburgh) , Amandine Bastide (M.R.C. Toxicology Unit, University of Leicester) , Tuija Pöyry (M.R.C. Toxicology Unit, University of Leicester) , Carolyn Jones (M.R.C. Toxicology Unit, University of Leicester) , Kate Dudek (M.R.C. Toxicology Unit, University of Leicester) , Geetanjali Patwardhan (School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham) , François Meullenet (School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham) , Neil J. Oldham (School of Chemistry, University of Nottingham) , Malcolm D. Walkinshaw (University of Edinburgh) , Anne E. Willis (M.R.C. Toxicology Unit, University of Leicester) , Peter M. Fischer (School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 124 , PAGES 200 - 217

State: Published (Approved)
Published: November 2016
Diamond Proposal Number(s): 1225

Open Access Open Access

Abstract: 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.

Journal Keywords: Cancer; eIF4E; Protein synthesis; mRNA translation; Cap-binding inhibitor

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography