Nuclear receptor (NR) liver receptor homologue-1 (LRH-1) is a potential target for the treatment of
breast cancers as a consequence of its regulation of aromatase and the estrogen receptor (ER).
Development of modulators of NRs historically focuses on production of high affinity small molecules
that compete for binding with natural ligands at the ligand-binding pocket (LBP) of the NR ligandbinding
domain (LBD). Ligand-bound NRs induce transcriptional activity by subsequent recruitment of
coactivator proteins.
The majority of this thesis describes approaches towards the development of the first antagonists of
LRH-1.
In the first instance, small molecules that bind at the LBP of the receptor were developed through use
of ligand-based virtual screening (VS) programs Cresset and SHop. Secondly, small molecules that
directly disrupt the binding of cofactor proteins to the NR activation function-2 (AF-2) were developed
through use of rational design and further Cresset VS.