Structural optimization of AR and AR-V7 degraders incorporating silicon-based hydrophobic tags for treatment of castration-resistant prostate cancer.

Androgen receptor splice variant 7 (AR-V7) plays a crucial role in the malignant progression of castration-resistant prostate cancer (CRPC). Current research has demonstrated that the development of novel AR-V7 degraders holds broad prospects and is expected to serve as a clinical therapeutic regimen for this disease. In the present work, we utilized structural analogs of enzalutamide to conjugate a silicon-containing hydrophobic tag (SiHyT) moiety via Click chemistry, achieving the selective degradation of the androgen receptor (AR) and AR-V7. Mechanistic studies revealed that the degrader disrupted the interactions between AR/AR-V7 and HSP90. This disruption further prompted the E3 ubiquitin ligase helicase-like transcription factor (HLTF) to recognize AR and AR-V7, followed by their ubiquitination and degradation in CRPC cell lines. Additionally, the active compound exhibited favorable pharmacokinetic properties and metabolic profiles. In both in vitro and in vivo experiments, this degrader displayed more potent activity than enzalutamide in inhibiting the proliferation and migration of CRPC cells. This study expands the application scope of the silicon-containing hydrophobic tag (SiHyT) strategy and provides an alternative design concept for the development of drugs targeting the degradation of AR/AR-V7 in the treatment of CRPC.