Novel Alpha-Helix Mimetics as Anti-Cancer Leads

Projektinformationen

NHELMIMACANL

ID Finanzhilfevereinbarung: 327114

Abgeschlossenes Projekt

Startdatum 6 Januar 2014

Enddatum 5 Januar 2016

Finanziert unter

• Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Gesamtkosten € 231 283,20

EU-Beitrag € 231 283,20

Koordiniert durch

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
United Kingdom

Ziel

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.

Wissenschaftliches Gebiet

• natural sciences › biological sciences › biochemistry › biomolecules › proteins › proteomics
• social sciences › sociology › demography › mortality
• medical and health sciences › clinical medicine › oncology › breast cancer

Programm/Programme

• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Thema/Themen

• FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development"

Aufforderung zur Vorschlagseinreichung

FP7-PEOPLE-2012-IEF
Andere Projekte für diesen Aufruf anzeigen

Finanzierungsplan

MC-IEF - Intra-European Fellowships (IEF)

Koordinator

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE

Kontakt Verwaltung

Brooke Alasya (Ms.)

• EU-Beitrag: € 231 283,20
• Adresse: SOUTH KENSINGTON CAMPUS EXHIBITION ROAD ; SW7 2AZ LONDON ; Vereinigtes Königreich
• Region: London › Inner London — West › Westminster
• Aktivitätstyp: Higher or Secondary Education Establishments
• Gesamtkosten: Keine Daten