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.
- 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: [email protected].
- 5. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
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.