Prostate cancer (PCa) is the most commonly diagnosed male cancer in North America, and the androgen deprivation therapy (ADT) is the mainstay of treatment for PCa by blocking the human androgen receptor (AR) or androgen synthesis. However, ADT invariably develops resistance when the disease progresses to a lethal form of castration-resistant PCa (CRPC). Currently, there is no curable treatment for CRPC, and thus, there is an urgent need for novel treatment of CRPC. The 52-kDa FK506-binding protein FKBP52 is an important positive regulator of the AR, glucocorticoid receptor (GR) and progesterone receptor (PR). The GR signaling has been known to confer resistance to current anti-AR treatments, and the PR antagonist was reported as a potential treatment for PCa. Thus, targeting FKBP52 with small-molecule inhibitors may lead to an effective therapeutic avenue for PCa by simultaneously hitting a variety of targets known to have a role in PCa. In this study, using structure-based <i>in silico</i> screening and molecular modeling against the peptidyl-prolyl isomerase site of FKBP52, we have identified a series of FKBP52-specific small-molecule inhibitors through biological evaluation, and the lead compound demonstrated potent inhibition of AR-mediated reporter gene expression, FKBP52-regulated AR activity, and AR-dependent PSA expression. These FKBP52-specific small-molecule inhibitors may have the potential to circumvent the ADT resistance and address the unmet need of novel therapy for CRPC.

In silico discovery of FKBP52 inhibitors as a prospective therapy for prostate cancer

249th National Meeting (2015)

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