Targeting the translational machinery in aggressive cancers
Eukaryotic initiation factor 4E (eIF4E) is a key focus in cancer research due to its central role in controlling the translation of tumour associated proteins that drive an aggressive migratory phenotype. eIF4E activity, modulated via its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and mitogen activated protein kinase interacting protein kinases (MNK1/2) The latter phosphorylates eIF4E on Ser209 whereas mTORC1 phosphorylates and de activates the eIF4E inhibitor, 4E BP1, to release translational repression. The work presented here describes the synthesis and characterisation of 4 (4 fluoro 2 isopropoxyphenyl)amino) 5 methyl thieno[2,3 d] pyrimidine 6 carboylic acid, known as compound 1, a MNK1/2 inhibitor. Further analysis of compound 1 in combination with mTORC1/2 inhibitors show that inhibiting these pathways simultaneously effectively slows the rate of cell migration in MDA MB 231 triple negative breast cancer (TNBC) cells. As an alternative approach, novel, cleavable dual MNK1/2 and PI3K/mTOR inhibiting hybrids were synthesised and characterised in MDA MB 231 cells. These were found to be less effective at slowing cell migration than the combination of individual inhibitors. Molecular modelling of compound 1 revealed a large hydrophobic pocket which was exploited with a bulkier ferrocene group. Two novel ferrocene containing compounds based upon compound 1 were synthesised and screened for MNK1/2 inhibition. To target migration more specifically, work was also carried out with an alternative translational protein, DDX3X. Both genetic knockdown and pharmacological inhibition alone and in combination with compound 1 reveal its potential as an anti cancer target.