FADI SOUKARIEH Fadi.Soukarieh@nottingham.ac.uk
Research Fellow
Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation
Soukarieh, Fadi; Nowicki, Matthew W.; Bastide, Amandine; Poyry, Tuija; Jones, Carolyn; Dudek, Kate; Patwardhan, Geetanjali; Meullenet, Fran�ois; Oldham, Neil J.; Walkinshaw, Malcolm D.; Willis, Anne E.; Fischer, Peter M.
Authors
Matthew W. Nowicki
Amandine Bastide
Tuija Poyry
Carolyn Jones
Kate Dudek
Geetanjali Patwardhan
Fran�ois Meullenet
NEIL OLDHAM NEIL.OLDHAM@NOTTINGHAM.AC.UK
Professor of Biomolecular Spectrometry
Malcolm D. Walkinshaw
Anne E. Willis
Peter M. Fischer
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 50 - terminal mRNA cap structure (m7 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 capbinding inhibitors of eIF4E by modifying the N7 -substituent of m7 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]-N0 -(2-methyl-propyl)-N-(phenylmethyl)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 m7 GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 50 -deoxy-50 -(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7 -methyl-guanosine (4a), N7 -3-chlorobenzyl-50 -deoxy-50 -(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7 -benzyl-50 -deoxy-50 -(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.
Citation
Soukarieh, F., Nowicki, M. W., Bastide, A., Poyry, T., Jones, C., Dudek, K., …Fischer, P. M. (2016). Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation. European Journal of Medicinal Chemistry, 124, 200-217. https://doi.org/10.1016/j.ejmech.2016.08.047
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 21, 2016 |
Online Publication Date | Aug 24, 2016 |
Publication Date | Nov 29, 2016 |
Deposit Date | Sep 23, 2016 |
Publicly Available Date | Sep 23, 2016 |
Journal | European Journal of Medicinal Chemistry |
Print ISSN | 0223-5234 |
Electronic ISSN | 1768-3254 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 124 |
Pages | 200-217 |
DOI | https://doi.org/10.1016/j.ejmech.2016.08.047 |
Keywords | Cancer; eIF4E; protein synthesis; mRNA translation; cap-binding inhibitor |
Public URL | https://nottingham-repository.worktribe.com/output/826653 |
Publisher URL | http://www.sciencedirect.com/science/article/pii/S0223523416307000 |
Contract Date | Sep 23, 2016 |
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0
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