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

Eur J Med Chem. 2026 Apr 5:307:118617. doi: 10.1016/j.ejmech.2026.118617.

Lei Xu ¹, Mengmeng Wang ², Yanshuo Cheng ³, Hanhan Kuang ³, Yijing Zhu ³, Ning Liu ³, Qianqian Wang ³, Shicong Li ⁴, Jiefu Wang ⁵, Junfeng Wang ⁶, Ziqi Huang ⁷, Ranlu Liu ⁸, Shuangwei Liu ⁹, Kun Zhang ¹⁰, Guang Yang ¹¹

Affiliations

1 Department of Urology, Tianjin Medical University General Hospital, Tianjin, 300052, China; Department of Urology, Zibo Central Hospital, Zibo, 255036, China.
2 College of Pharmacy, Nankai University, Tianjin, 300071, China. Electronic address: [email protected].
3 College of Pharmacy, Nankai University, Tianjin, 300071, China.
4 Department of Urology, Tianjin Medical University General Hospital, Tianjin, 300052, China. Electronic address: [email protected].
5 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. Electronic address: [email protected].
6 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. Electronic address: [email protected].
7 College of Pharmacy, Nankai University, Tianjin, 300071, China. Electronic address: [email protected].
8 Department of Urology, Tianjin Medical University General Hospital, Tianjin, 300052, China. Electronic address: [email protected].
9 College of Pharmacy, Nankai University, Tianjin, 300071, China. Electronic address: [email protected].
10 College of Pharmacy, Nankai University, Tianjin, 300071, China; Institute of Chemistry, Henan Academy of Sciences, Zhengzhou, 450002, China. Electronic address: [email protected].
11 College of Pharmacy, Nankai University, Tianjin, 300071, China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China. Electronic address: [email protected].

PMID: 41666761 DOI: 10.1016/j.ejmech.2026.118617

Abstract

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.

Keywords

AR/AR-V7; Castration-resistant prostate cancer; HLTF; Silicon-based hydrophobic tags; Targeted protein degradation.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-181727

AR/AR-V7 degrader-1

AR/AR-V7 Degrader

Androgen Receptor; HSP; CDK

Cancer

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