2. Academic Validation
  3. Discovery of highly potent AKR1Cs pan-inhibitors as chemotherapeutic potentiators to restore breast cancer drug resistance

Discovery of highly potent AKR1Cs pan-inhibitors as chemotherapeutic potentiators to restore breast cancer drug resistance

  • Eur J Med Chem. 2025 May 5:289:117413. doi: 10.1016/j.ejmech.2025.117413.
Shuaishuai Xing 1,  Yijun Liu 1,  Huanfang Xie 1,  Can Guo 1,  Xiaolong Wang 1,  Bingbing Lv 2,  Xinyu Li 1,  Jikuan Shao 1,  Qinglong Guo 3,  Feng Feng 4,  Haopeng Sun 5
Affiliations

Affiliations

  • 1 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 2 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, 210009, People's Republic of China; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
  • 4 School of Pharmacy, Nanjing Medical University, 211166, Nanjing, People's Republic of China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 5 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: sunhaopeng@cpu.edu.cn.
PMID: 40015157 DOI: 10.1016/j.ejmech.2025.117413
Abstract

The acquired resistance of doxorubicin (DOX) significantly limits their application in breast Cancer treatment. In earlier investigations, a pan-inhibitor, S07-2010, exhibiting inhibitory activity against Aldo-Keto Reductase 1C1-1C4 (AKR1C1-1C4) was discovered through virtual screening. In this study, four rounds of structural modifications were conducted, and the optimized compound 29 exhibited potent inhibitory activity against AKR1C1-1C4 (AKR1C1 IC50 = 0.09 μM, AKR1C2 IC50 = 0.28 μM, AKR1C3 IC50 = 0.05 μM, AKR1C4 IC50 = 0.51 μM). Molecular dynamics (MD) simulations revealed that 29 consistently occupied both SP2 and SP3 pockets, which may explain its pan-inhibitory activity. Utilizing highly DOX resistant MCF-7/ADR cells, 29 demonstrated superior potential as a therapeutic agent for re-sensitizing drug-resistant cell lines to chemotherapy both in vitro and in vivo, suggesting that pan-inhibition of AKR1C1-1C4 may serve as a more promising therapeutic strategy for drug-resistant breast Cancer. In summary, Compound 29 may be a promising therapeutic Adjuvant in the development of novel strategies to overcome drug resistance.

Keywords

AKR1Cs pan-inhibitors; Adjuvant effects; Breast cancer; Drug resistance.

Figures
Products