Design, Synthesis, and Biological Evaluation of Androgen Receptor (AR) Antagonist-Heat Shock Protein 90 (Hsp90) Inhibitor Conjugates for Targeted Therapy of Castration-Resistant Prostate Cancer

Abstract

Androgen deprivation in cases of castration-resistant prostate cancer (CRPC) leads to adverse effects, including loss of muscle and bone mass and gain of subcutaneous fat. The tumor-specific suppression of androgen receptor (AR) signaling, while not global, may reduce side effects. We present a class of small-molecular conjugates consisting of an AR antagonist linked to a heat shock protein 90 (Hsp90) inhibitor. We demonstrate that the high accumulation of Hsp90 on the surface of CRPC cells allows uptake of conjugates and increases the enrichment of drugs in the tumor cells. After penetrating prostate cancer cells, the conjugates not only inhibit AR function by the antagonist component but also bind to Hsp90 and suppress the AR protein level. Compared to AR antagonists, these conjugates showed improved tumor-targeting ability and enhanced potency against Enzalutamide-resistant 22Rv1 cells.

Discovery of BWA-522, a First-in-Class and Orally Bioavailable PROTAC Degrader of the Androgen Receptor Targeting N-Terminal Domain for the Treatment of Prostate Cancer

“…An animal body weight loss of 16% was observed in vehicle groups (Figure C). The weight loss observed in the control group aligns with earlier reports from our and other groups. ,− In comparison with vehicle control, BWA-522 at 20 and 60 mg/kg did not result in noticeable weight loss throughout the entire experiment, indicating that it was well tolerated by mice.…”

“…MTX-23 ( 12 ), the first AR-DBD-targeted PROTAC compound, was reported to degrade full-length AR (AR-FL) and AR-V7 effectively with DC 50 values of 2 and 0.37 μM, respectively . Our group has recently reported small-molecule conjugates containing an AR antagonist, a chemical linker, and an Hsp90-binding motif capable of inducing AR-FL and AR-V7 degradation . We hypothesized that PROTACs targeting AR-NTD should be able to degrade AR-FL and AR-V7 simultaneously and will show clinical value in the treatment of PC and CRPC.…”