Prostate cancer affects one in seven men in the United States and is a major leading cause of cancer death among men. Current treatment strategies exploit the dependence of AR for hormone activation and current therapies are ineffective in castration resistant prostate cancer CRPC. Based on this rationale, we are pursuing a unique non-AR based strategy. The folding, activation, and nuclear translocation of steroid hormone receptors involves no less than twelve proteins and at least four distinct complexes. At least one of these proteins, the FKBP52 cochaperone, is a highly promising therapeutic target for the disruption of a number of mechanisms important in prostate cancer. The proposed research is focused on the preclinical development of GMC1, a drug-like small molecule that targets FKBP52 regulation of steroid hormone receptor activity. During the first year of this award we have made progress in the hit-to-lead optimization process and have identified a number of novel derivatives with activity. We have also established protocols and assays for assessing lead drug effects in cellular and animal models.