Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- social sciences sociology demography mortality
- medical and health sciences clinical medicine oncology breast cancer
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2012-IEF
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Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
SW7 2AZ London
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.