The aim of this project is the structure-based design, synthesis, and evaluation of small-molecule coactivator binding inhibitors (CBIs), compounds which bind to the surface of the estrogen and androgen receptors (ER and AR) and directly inhibit the nuclear hormone receptor(NHR)/coactivator interaction. Traditional antagonists of these receptors, which bind in the internal ligand binding pocket of ER and AR, have long been used to treat hormone-responsive breast and prostate cancers, respectively. Although these drugs produce initial tumor regression, in a relatively short amount of time (months to a few years) mutations and modifications in protein regulation eventually allow the cancer cell to circumvent this inhibition, leading to uncontrolled tumor progression. Nevertheless, even in this hormone-refractory state, the carcinomas continue to be ER and AR-dependent. Consequently, these receptors remain important targets for breast and prostate cancer therapies. It is hypothesized that CBIs, due to their direct inhibitory nature, could prove an effective endocrine therapy even after the failure of traditional antagonists. In addition to their possible utility as cancer therapeutics, these compounds should be of interest to molecular endocrinologists as cell- permeable probes that allow for further investigation of the NHR/coactivator complex. This project aims to build on the successes we have recently achieved in the NHR CBI area, especially those of the pyrimidine- core class of CBIs, members of which are modest ERa and AR/coactivator disrupters. To accomplish this, multiple, small CBI libraries will be synthesized, including compounds based on a tetra-aryl cyclobutane core that has already shown promising binding characteristics. Various heterocyclic and ter-pyrimidine scaffolds will also be used as core motifs. Current and future crystallographic efforts will be used to elucidate the nature of the NHR/CBI interaction, which in turn will allow for the structure-based design of second- generation CBI libraries. All synthesized compounds will be assayed for their CBI activity using in vitro and cell-based methods, which will determine inhibitory activity as well as confirm binding to the surface of the receptor. With this three-pronged approach, it is hoped that the development of ER and AR-selective CBIs with affinities in the nanomolar range will be achieved. Due to the ability of breast and prostate cancers to overcome inhibition brought about by traditional estrogen and androgen receptor antagonists, novel approaches are needed to effectively treat these cancers. By binding to the surface of the receptor, coactivator binding inhibitors or CBIs offer a new approach to endocrine-related cancer therapy, one that should remain viable after current antagonists fail.