| Summary: | Breast cancer is the most common cancer in women worldwide and afflicts about 30 % of all women between 35 and 50 years. The majority of breast cancers are estrogen dependent. This means that they need estrogen for their development and growth. Estrogen dependent breast cancers can be treated with hormone therapy to block estrogen action and prevent cancer growth. Unfortunately, there are many side effects associated with this treatment and therefore, there is a great need for the development of new therapies for breast cancer. Liver receptor homologe-1 (LRH-1) is a nuclear receptor that recently came into focus for its implications in breast cancer development and growth. Targeting LRH-1 could present an alternative approach for the treatment of breast cancer. There are two potential sites to target nuclear receptors: the ligand binding pocket or the co-activator binding site. Both sites are known to be crucial for the transcriptional activity of nuclear receptors. This thesis gives an overview about breast cancer and the role of nuclear receptors in this disease. In particular, approaches to the regulation of nuclear receptors using small molecule antagonists are discussed both in terms of traditional 'ligand binding pocket' inhibitors and the more recently explored 'co-activator binding inhibitors'. Both approaches are explained generally and in the context of LRH-1. The work described here is divided into two parts: The first part describes the synthesis and evaluation of a library of benzimidazole-based potential antagonists of LRH-1. These molecules are expected to bind into the ligand binding pocket and act as traditional antagonists. The second part of this thesis explains the synthesis of an α-helix mimetic. A previous PhD student in the group developed a route for the synthesis of an α-helix mimetic. The mimetic targeted here was anticipated to bind competitively to the co-activator binding site of LRH-1 and prevents co-activators from binding and consequently blocks transcriptional activity.
|
|---|
