Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancer

Chiu Lien Hung, Hao Hsuan Liu, Chih Wei Fu, Hsun Hao Yeh, Tsan Lin Hu, Zong Keng Kuo, Yu Chin Lin, Mei Ru Jhang, Chrong Shiong Hwang, Hung Chih Hsu, Hsing Jien Kung, Ling Yu Wang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

9 Scopus citations


Background: Despite the advent of improved therapeutic options for advanced prostate cancer, the durability of clinical benefits is limited due to inevitable development of resistance. By constitutively sustaining androgen receptor (AR) signaling, expression of ligand-binding domain truncated AR variants (AR-V(ΔLBD)) accounts for the major mechanism underlying the resistance to anti-androgen drugs. Strategies to target AR and its LBD truncated variants are needed to prevent the emergence or overcome drug resistance. Methods: We utilize Proteolysis Targeting Chimeras (PROTAC) technology to achieve induced degradation of both full-length AR (AR-FL) and AR-V(ΔLBD) proteins. In the ITRI-PROTAC design, an AR N-terminal domain (NTD) binding moiety is appended to von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase binding ligand with linker. Findings: In vitro studies demonstrate that ITRI-PROTAC compounds mechanistically degrade AR-FL and AR-V(ΔLBD) proteins via ubiquitin-proteasome system, leading to impaired AR transactivation on target gene expression, and inhibited cell proliferation accompanied by apoptosis activation. The compounds also significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy. Interpretation: AR NTD that governs the transcriptional activities of all active variants has been considered attractive therapeutic target to block AR signaling in prostate cancer cells. We demonstrated that utilizing PROTAC for induced AR protein degradation via NTD represents an efficient alternative therapeutic strategy for CRPC to overcome anti-androgen resistance. Funding: The funding detail can be found in the Acknowledgements section.

Original languageEnglish
Article number104500
Pages (from-to)104500
StatePublished - 04 2023

Bibliographical note

Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.


  • AR
  • AR-V7
  • Castration resistant prostate cancer
  • Enzalutamide resistance
  • Humans
  • Nitriles/therapeutic use
  • Male
  • Proteolysis Targeting Chimera
  • Receptors, Androgen/genetics
  • Proteolysis
  • Cell Line, Tumor
  • Ligands
  • Prostatic Neoplasms, Castration-Resistant/drug therapy


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