B-Cell Lymphoma 3 (Bcl-3) is a proto-oncogene modulating the nuclear factor κB (NF-κB) signalling pathway, which had been first identified at the site of a t (14,19) translocation in B-cell chronic lymphocytic leukemia. Deregulated Bcl-3 expression has been reported in various tumours and in breast tumours Bcl-3 was found to be significantly elevated compared to the normal adjacent tissue. Activated NF-кB signalling is detected in 86% of ER-negative and HER2+ breast tumours. The currently used monoclonal antibody against HER2 (trastuzumab), produces remissions in 10-15 % of HER2+ breast cancers, thus the identification of novel therapeutic targets is essential. Previous in vivo studies used ErbB2 (MMTV/neu) mouse models deficient in Bcl-3 to understand the role and underlying mechanism of Bcl-3 in mammary tumour formation and progression. Even though Bcl-3 deficiency in vivo did not affect the primary tumor growth, the occurrence of developed lung metastases was reduced by 40%. Despite these effects on tumour progression, no effect on normal mammary gland function was observed. Based on the this evidence, the inhibition of Bcl-3 seems a promising therapeutic strategy, especially for HER2+ breast cancers, mainly in the prevention of secondary-tumour seeding and spread at distal sites. Using a Bcl-3 binding mutant we have shown that Bcl-3 function can be inhibited by disruption of binding to its cognate partners, p50 and p52 from the NF-κB family. Using molecular modelling we constructed a model of the Bcl-3-p50 complex, identified a novel protein-protein interaction domain and performed initial virtual screening for potential small molecule inhibitors. Candidate compounds were evaluated in human tumorigenic (MDA-MB-231) and non-tumorigenic cell lines (HEK-293) in cell based assays determining the effect on disruption of Bcl-3—p50 binding, as well as the change in NF-κB activity and migration ability. A lead compound was identified with low nM activities in all three cell based assays. Analogues of the lead compound were designed and synthesized in order to evaluate the structure-activity relationships (SAR). Important moieties in the structure were identified and the structural analogue 15f had almost 10 fold increase in the activity over the lead compound. More structural analogues will be analysed in the near future to further explore the SAR of the lead compound. Meanwhile in vivo xenografts experiments are evaluating the efficacy of the lead compound and its analogue 15f on the ability to suppress the spread and growth of secondary tumours.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:585288 |
| Date | January 2013 |
| Creators | Soukupová, Jitka |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/52578/ |
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