VPC-13822 - A Novel Nonsteroidal Drug for the Treatment of Castration Resistant Prostate Cancer by Blocking the Binding Function-3 of the Human Androgen Receptor.

Inhibition of the alternative target site Binding Function-3 (BF3) of the androgen receptor (AR) with small molecules may represent a novel and viable option for treating castration-resistant disease. In vitro transcription assays and microsome stability experiments were used to characterize the latest and most optimized AR BF3 inhibitor compound VPC-13789 to determine its anti-AR activity and pharmacokinetic properties. VPC-13789 selectively inhibited AR-mediated transcription with an IC50 value of 0.2 µM and effectively supressed the growth of androgen-stimulated LNCaP cell line with an IC50 of 0.32 µM while having no effect on AR-negative PC3 cells. We have further synthesized a pro-drug of VPC-13789 (VPC-13822) with improved solubility and bioavailability. The VPC-13822 pro-drug was evaluated for 4 weeks in mice xenograft LNCaP castration resistant model. When administered orally, VPC-13822 significantly reduced PSA production and tumor volume in this prostate cancer model. No signs of generic toxicity of the candidate compound were observed. Taken together, these results establish a novel class of orally available AR inhibitors with a completely distinct mode of action with a potential utility to treat drug-resistant forms of prostate cancer. Overall design: Polyadenylated RNA profiles of LNCaP cells treated with treated with ethanol (ETOH) plus DMSO, or dihydrotestosterone (DHT) plus either DMSO (Control), Enzalutamide, or VPC-13789, in three biological replicates, obtained using BGISeq500 platform.