Resistance to anti-androgen therapy is associated with increased expression of androgen receptor (AR) mRNA, AR gene amplification or AR mutation. Increased AR levels are necessary and sufficient to promote hormone-refractory growth in models and, paradoxically, alter the cellular response to classic AR antagonists such that they function as weak agonists. Therefore, second generation anti-androgens must overcome these resistance mechanisms. We searched for novel AR antagonists that might retain function in the context of increased AR expression through a cell-based screen. Using the high affinity AR agonist RU59063 as a starting point, we synthesized and screened over 200 compounds to construct a structure/activity profile that defines features of the scaffold essential for receptor binding and for maximal antagonism. We focused our further efforts on a novel compound RD162, which retains potent anti-androgen activity in cells expressing increased levels of AR, blocks AR function in mice and impairs the growth of LNCaP and LAPC-4 xenografts engineered to express high levels of AR, whereas bicalutamide had minimal activity. RD162 inhibits AR with 10-fold greater affinity than bicalutamide and functions through a novel mechanism of action that impairs nuclear translocation and DNA binding. An RD162 derivative MDV3100 has shown clinical activity in a Phase I-II clinical trial of ~140 men with castrate-resistant prostate cancer. About 50 percent of patients have had reductions of PSA by greater than 50% sustained for more than 12 weeks, including some men with radiographic responses and a much larger proportion with stable disease. A phase III trial of MDV3100 in men with castration resistance, chemotherapy refractory prostate cancer was initiated in September, 2009.