Tumour Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) is a protein belonging to the TNF family of ligands. TRAIL is able to induce apoptosis in tumour cells, whilst leaving normal cells unaltered, representing therefore an attractive anti-cancer agent. In breast cancer, however, different cell lines are resistant to TRAIL. Moreover, many studies have demonstrated that breast cancer stem cells (bCSCs), the cells that are the most responsible for relapses and metastasis development, are resistant to TRAIL. Cellular FLICE-Like Inhibitory Protein (c-FLIP) plays a crucial role in TRAIL-resistance due to its ability to interfere with the TRAIL pathway, preventing therefore the apoptosis. In the course of a previous study, the homology model of c-FLIP has been constructed and using a structure-based virtual screening of commercially available compounds, one hit compound (3) able to inhibit c-FLIP at micromolar concentrations has been identified. Starting from the structure of the hit compound, several new derivatives belonging to four different structural families were designed and synthesised: sulfonamide derivatives, amine derivatives, amide derivatives and methylene derivatives. All the newly synthesised compounds were tested in an in vitro assay for their ability to sensitise TRAIL-resistant MCF-7 breast cancer cell line to TRAIL. Different derivatives retained the ability to increase TRAIL sensitisation showing a similar or slightly improved activity compared to the original hit. Some of the most promising compounds were further evaluated in in vitro pharmacokinetic assays, dose-response and cytotoxicity studies. The results obtained from these studies suggested the identification of a novel hit compound (88) which showed the ability to increase TRAIL sensitisation with an IC50 value in the range of 15-19 μM and improved metabolic stability compared to 3. Additionally, molecular docking analyses suggested a potential ability of the newly synthesised derivatives to occupy the pocket of c-FLIP. Taking into consideration all these results, a series of novel potential small molecule c-FLIP inhibitors showing ability to increase TRAIL sensitisation in resistant breast cancer cells and breast cancer stem cells was developed.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:742882 |
| Date | January 2018 |
| Creators | Giancotti, Gilda |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/111577/ |
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