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Discovery of Bcl-3 inhibitors for the potential treatment of metastatic breast cancer

Bordoni, Cinzia 2016. Discovery of Bcl-3 inhibitors for the potential treatment of metastatic breast cancer. PhD Thesis, Cardiff University.
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Abstract

In HER-2 positive metastatic breast cancer, the proto-oncogene Bcl-3 was found to be overexpressed. Bcl-3 acts as a transcriptional co-activator: it forms a ternary complex with DNA and homodimer (p50)2 and stimulates the transcription of a different panel of genes in the metastatic progression of the breast cancer. Its exact role in endogenous tumours is still unknown. In vivo knockdown studies shown, that Bcl-3 deficiency did not affect the primary tumour, but it reduced the occurrence of metastases by 80% without any effects on the normal mammary gland function. Patients with this type of tumour have a poor prognosis, do not respond to the typical treatment or show resistance and side effects to the usual therapeutic options. Hence, there is an urgent need to find new candidate drugs. A virtual screening targeted against a newly identified Bcl-3 binding pocket allowed the identification of 10 molecules, tested in vitro cell based assays. Four molecules were active. In this thesis, different analogues of these four hit compounds were synthesised. Based on docking studies, another two scaffolds were designed. The non-cytotoxic profile of the new analogues was assessed using the cell titer blue assay. The activity of the compounds was established using the colony forming assay (CFA). To prove the Bcl-3/p50 interaction, immunoprecipitation and co-immunoprecipitation were performed. None of the compounds was cytotoxic. Some of them exhibited a promising activity in the CFA. One molecule exhibited an interesting activity profile both in vitro and in vivo and in pharmacokinetic studies and it has been forwarded into full pre-clinical development

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Bcl-3 inhibitors; metastatic; breast cancer
Date of First Compliant Deposit: 6 February 2017
Last Modified: 12 Jun 2019 02:59
URI: http://orca-mwe.cf.ac.uk/id/eprint/97999

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