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April 19, 2026Cancer Research

Abstract NG10: First-in-class dual AR/AR-V7 molecular glue degraders targeting the undruggable N-terminal domain to overcome therapeutic resistance in prostate cancer

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Authors

CACheukMan C. AuMNMichelle NaidooCECatrina Estrella

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Overview

Research demonstrates effective degradation of AR-V7 and AR in prostate cancer, suggesting a breakthrough strategy to overcome therapeutic resistance.

Key Points

  • The research aims to develop a first-in-class molecular glue degrader that targets AR and AR-V7 to combat therapeutic resistance in prostate cancer.
  • Conducted a high-throughput screen of 170,000 small molecules.
  • Optimized lead compounds through medicinal chemistry and SAR analysis.
  • Evaluated the efficacy of compounds in vivo using xenograft models.
  • Performed pharmacodynamic studies to assess protein degradation.
  • Utilized CRISPR-based E3 ligase screens for mechanistic insights.
  • Identified lead compounds with IC50 <10 nM and significant tumor growth suppression in resistant models.
  • Achieved near-complete degradation of AR and AR-V7 within 24 hours of treatment.
  • Demonstrated >10-fold higher efficacy compared to the existing AR degrader ARV-110.
  • Confirmed a novel binding mechanism to the N-terminal domain of AR and AR-V7.

Cite This Study

Au et al. (2026) studied this question.

synapsesocial.com/papers/69e47220010ef96374d8e56fhttps://doi.org/10.1158/1538-7445.am2026-ng10
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