2. Academic Validation
  3. Discovery of a highly potent, N-terminal domain-targeting degrader of AR-FL/AR-V7 for the treatment of prostate cancer

Discovery of a highly potent, N-terminal domain-targeting degrader of AR-FL/AR-V7 for the treatment of prostate cancer

  • Eur J Med Chem. 2025 Jan 15:282:117079. doi: 10.1016/j.ejmech.2024.117079.
Si Ha 1,  Chenxuan Ji 1,  Jiaqi Yang 1,  Maoxu Xiao 1,  Ziyi Xu 2,  Wei-Wei Pan 3,  Hua Xiang 4,  Guoshun Luo 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 Department of Chemistry, Boston University, Boston, MA, 02215, United States.
  • 3 Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing, 314001, China.
  • 4 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: xianghua@cpu.edu.cn.
  • 5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: gsluo@cpu.edu.cn.
PMID: 39577229 DOI: 10.1016/j.ejmech.2024.117079
Abstract

The clinical development of PROTACs targeting the Androgen Receptor (AR) for degradation has made significant progress. However, effective treatments for metastatic prostate cancers containing the Androgen Receptor splice variant 7 (AR-V7), a constitutively active mutant without the ligand-binding domain (LBD), are still lacking. Here, we reported the identification of a highly potent, noncovalent PROTAC targeting the N-terminal domain (NTD) of AR, NP18, which is developed from the covalent AR-NTD antagonist EPI-002, and effectively degrades both AR-FL and AR-V7 in 22Rv1 cells (DC50: 18 and 26 nM respectively). Mechanistically, NP18 interacts with the N-terminal domain (NTD) of both full-length AR (AR-FL) and splice variant 7 (AR-V7), leading to their selective and proteasomal degradation. Importantly, NP18 exhibited remarkably superior antitumor activity in both 22Rv1 xenograft and patient-derived xenograft (PDX) models than EPI-002. Taken together, these findings highlight NP18 as a promising candidate to counteract AR splice variant-driven resistance.

Keywords

Androgen receptor; Androgen receptor splice variant 7; PROTAC; Prostate cancer.

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