Objectif Breast cancer is the most common cancer in women in the western world, and 80% of breast cancers express the estrogen receptor (ER). Whilst inhibitors of ER action such as Tamoxifen and inhibitors of estrogen biosynthesis (e.g. aromatase inhibitors such as Anastrozole) have contributed to reductions in breast cancer mortality, resistance to these agents is a major problem. Such resistance could potentially be minimised by switching therapy with endocrine agents and as such there is an urgent clinical need to identify potent inhibitors of novel targets focused on countering endocrine resistance.Liver receptor homologue 1 (LRH-1) is a nuclear receptor (NR) protein whose transcriptional activity is critical for aromatase expression in tissue surrounding the tumour. Moreover, LRH-1 also directly regulates breast cancer cell growth acting in concert with ER. Development of selective LRH-1 inhibitors would therefore provide a potent means of inhibiting ER activity in breast cancer cells, by direct down-regulation of ER levels and prevention of its activation by inhibiting local estrogen biosynthesis.In this project, we plan to develop selective LRH-1 inhibitors by synthesising small molecule Coactivator Binding Inhibitors (CBIs) that will block the protein-protein interaction between LRH-1 and its coactivator proteins (e.g. SHP-1). This interaction is an obligatory prerequisite for transcriptional activity. The critical binding interface comprises an alpha-helical secondary structural motif presented on the surface of the coactivator and a complimentary surface exposed groove in the AF-2 domain of LRH-1. Five key residues on the alpha-helix are required for potent and selective binding. Thus the molecules we will prepare by organic synthesis and evaluate initially in both FRET binding and cell-based gene-reporter assays as LRH-1 antagonists will comprise of structurally novel 5-residue-presenting alpha-helix mimetics. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicssocial sciencessociologydemographymortalitymedical and health sciencesclinical medicineoncologybreast cancer Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Appel à propositions FP7-PEOPLE-2012-IEF Voir d’autres projets de cet appel Régime de financement MC-IEF - Intra-European Fellowships (IEF) Coordinateur IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Contribution de l’UE € 231 283,20 Adresse SOUTH KENSINGTON CAMPUS EXHIBITION ROAD SW7 2AZ LONDON Royaume-Uni Voir sur la carte Région London Inner London — West Westminster Type d’activité Higher or Secondary Education Establishments Contact administratif Brooke Alasya (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée