Targeting the translational machinery in aggressive cancers

Lineham, Ella Kim (2019) Targeting the translational machinery in aggressive cancers. Doctoral thesis (PhD), University of Sussex.

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Abstract

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.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens > RC0261 Cancer and other malignant neoplasms
Depositing User: Library Cataloguing
Date Deposited: 15 May 2019 08:54
Last Modified: 15 May 2019 08:54
URI: http://sro.sussex.ac.uk/id/eprint/83783

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