LRH-1 is an orphan nuclear receptor that has been implicated in breast cancer progression due to its ability to stimulate aromatase expression, thereby increasing the availability of estrogen for estrogen receptor (ER)+ve tumour growth (Clyne et al., 2002). Recent studies also show that LRH-1 overexpression helps to recruit ER-α to its target sites (Lai et al., 2013) as well as improve motility and invasion of breast cancer cells contributing to metastasis (Chand et al., 2010). Current hormone therapies that inhibit aromatase or modulate ER action (SERMs) are effective but have also been associated with significant adverse effects, due to global inhibition of estrogen action. These include bone loss, joint pain, and possibly cognitive disturbances and compromised liver function.

Since LRH-1 is expressed in breast cancer cells and regulates aromatase in breast cancer, ovary and adipose tissues (Clyne et al., 2004), inhibition of LRH-1 action would provide an anti-estrogen therapy with fewer side effects compared to current treatments. LRH-1 has no known ligands that act as pharmacological antagonists. It is however, regulated by co-activators and co-repressors that bind to a co-regulator site. We screened virtual compound libraries against this co-regulator site of a published 3D crystal structure of the LRH-1 (Sablin et al., 2003) to select a few hundred candidate molecules. These small molecular weight compounds were tested in functional assays and we have identified three different classes of active compounds. Two of these compound classes have been docked into the co-regulator site and a third class to an alternate phospholipid binding site. Our aim is to determine the interactions of the current compounds with LRH-1 by crystallography, functional assays and SPR, and use that information to improve the potency and specificity of these compounds towards LRH-1