Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Androgen receptor (AR) antagonists play important roles
in the
treatment of castration-resistant prostate cancer (CRPC). The glucocorticoid
receptor (GR) upregulation leads to drug resistance for clinically
used antiandrogens. Therefore, blocking AR/GR signaling simultaneously
has become an efficient strategy to overcome the drug resistance of
CRPC. Our previous work indicated that Z19 could inhibit
the activity of both AR and GR. Herein, we optimized the structure
of Z19 and identified GA32 as a potent AR/GR
dual inhibitor. GA32 efficiently reduced the mRNA and
protein levels of AR/GR downstream genes. GA32 efficiently
inhibited the proliferation of enzalutamide resistance CRPC both in
vitro and in vivo. GA32 could directly bind to AR and
GR, and the predicted binding modes for GA32 with AR/GR
suggested that GA32 binds to the AR or GR hormone binding
pocket. This work provides a potential lead compound with dual AR/GR
inhibitory activity to conquer the drug resistance of CRPC.