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

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.