Antiandrogen Equipped Genistein Conjugates Facilitate Androgen Receptor Downregulation in Prostate Cancer

Abstract

Prostate cancer is the second most leading cause of cancer-related death among American men. The expression of androgen receptor protein has been established by numerous studies as a main driving force for the progression of prostate cancer. In an effort to combat this disease, potent compounds such as genistein have been identified to have significant anti-cancer activity and androgen receptor modulation in prostate cancer cells. Furthermore, studies have shown that antiandrogen ligands may be functionalized with hydrophobic moieties to selectively degrade androgen receptor protein in vitro. Building upon these findings, this study explores the efficacy of a bifunctional molecule; specifically a combination of a potent, non-steroidal enzalutamide-derived antiandrogen with genistein acting as a partially hydrophobic degradation tag. Preliminary cell viability studies have identified a promising lead compound (compound 9b) within the synthesized conjugates. This compound exhibits potent inhibition of cell growth in androgen sensitive LNCaP cells (IC50 = 1.44 ± 0.9 µM), and androgen insensitive DU145 cells (IC50 = 3.38 ± 0.9 µM). Western immunoblotting studies confirm the dose-dependent degradation of androgen receptor and cell cycle analyses indicate S-phase arrest with the treatment of compound 9b. While preliminary immunoblotting studies suggest the degradation of androgen receptor is mediated by the ubiquitin protease system, further studies must be carried out to validate these preliminary results. Future studies include looking into androgen receptor binding efficacy with the addition of the genistein moiety and the effect of the target compounds on the metastatic potential of bone-derived (PC3) prostate cancer cells.