Lineham, Ella Kim.pdf (8.02 MB)
Targeting the translational machinery in aggressive cancers
thesis
posted on 2023-06-09, 17:48 authored by Ella LinehamEukaryotic 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.
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- Published version
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219.0Department affiliated with
- Biochemistry Theses
Qualification level
- doctoral
Qualification name
- phd
Language
- eng
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University of SussexFull text available
- Yes
Legacy Posted Date
2019-05-15Usage metrics
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