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Title: Synthesis of inhibitors of the IKK-complex for the treatment of prostate cancer
Author: Baiget, Jessica
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2012
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Prostate cancer is the second most prevalent cancer in men. Activation of the NF-ҡB pathway is involved in the development of prostate cancer resistance to current therapies and contributes to the high mortality rate associated with this cancer. NF-ҡB has been shown to be inactive in the cytosol when bound with IҡB proteins. Activation of the IҡB kinase (IKK) complex degrades IҡB via phosphorylation and subsequent targeting by the proteasome, which enables transcription of NF-ҡB into the nucleus to control gene expression. The IKK-complex is formed by the two catalytic subunits IKKα and IKKβ and a regulatory subunit, NEMO, which is essential for its activation. The key interaction between these three units occurs in a localised region characterised by a hexapeptide sequence (LDWSWL). Disruption of the IKK-complex suppresses the transcription of NF-ҡB and can suppress tumour development. This project focuses on the suppression of this pathway using two different approaches. Firstly, the disruption of the interaction of NEMO with the two catalytic subunits was attempted using short modified-hexapeptide sequences based upon LDWSWL. We sequentially varied the six residues to identify the most efficacious sequence that disrupts the IKK-complex with the view to producing drug-like peptidomimetics with increased stability, potency and an improved pharmacokinetic profile. The synthesis of these novel peptides was accomplished by solid phase peptide synthesis and using SP-HPLC for their purification. A novel and simple method based fluorescence techniques was investigated to evaluate the interaction of NEMO with these hexapeptide sequences. The second approach to disrupt NF-ҡB activation was investigated by designing and developing selective heterocyclic ATP competitive inhibitors against IKKα and IKKβ. β-carbolines are known to be selective inhibitors of IKKβ, but other carboline-derived scaffolds (α-, γ- or δ-carbolines) have not yet been explored. Our efforts have been focussed on the synthesis of these scaffolds and to produce potent and selective drug-like molecules for the inhibition of IKKα and IKKβ. Our results have shown that a derivative of β-carboline inhibits IKKβ with high potency and selectivity and that the α-carboline offers an extremely promising scaffold for the synthesis of very potent IKKα-inhibitors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available