Novel Small Molecule Antagonists of the Interaction of the Androgen Receptor and Transcriptional Co-regulators

摘要

Androgens, mediated by the Androgen Receptor (AR), play a crucial role in prostate cancer. Current treatments are focused on anti-androgenic drugs competing with natural androgens and antagonizing the transcriptional activity of the AR. Although widely used, these drugs have shown significant side effects and in addition, tumors have become resistant suggesting mutations of the receptor. Regulation of gene expression by AR requires the binding to androgens or to its natural ligand, dihydrotestosterone (DHT), and assembly of coregulatory proteins (CoR). The blockage of the interaction between DHTliganded AR and CoR by small molecules has been shown to inhibit gene transcription. Thus, novel approaches to inhibit AR activity by means other than ligand binding could have a significant clinical impact. Preliminary data revealed that non-steroidal anti-inflammatory drugs, like flufenamic acid (FLF), block AR transcriptional activity but don't displace androgens. We developed small molecule structural analogs of FLF that inhibit AR transcription activity in the nanomolar range and act on AR target genes. We demonstrated an AR antagonism in vitro (transcription assays, binding assays) that is different from ligand competition. Multiple lines of evidence presented here suggest that compounds function by a distinct mechanism than the current marketed anti- androgens (drug combination studies). An early pharmacological profile of these small inhibitors has been characterized (cytotoxicity, cell permeability). We provide the first class of small molecules able to inhibit AR transcription activity without androgen competition. Those small molecule inhibitors represent powerful assets to study the mechanism of AR transcriptional function and a new potential therapeutic modality for prostate cancer treatment.