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  3. Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer

Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer

  • Eur J Med Chem. 2023 Feb 5;247:115013. doi: 10.1016/j.ejmech.2022.115013.
Yang Liu 1,  Yuting Chen 2,  Jiheng Jiang 3,  Xianglin Chu 2,  Qinglong Guo 4,  Li Zhao 4,  Feng Feng 5,  Wenyuan Liu 2,  Xiaolong Zhang 6,  Siyu He 7,  Peng Yang 8,  Pengfei Fang 9,  Haopeng Sun 10
Affiliations

Affiliations

  • 1 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China; Academy for Advance Interdisciplinary Studies, Peking University, Beijing, 100871, People's Republic of China.
  • 2 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
  • 3 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
  • 5 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China; Jiangsu Food and Pharmaceuticals Science College, Institute of Food and Pharmaceuticals Research, 223005, People's Republic of China.
  • 6 Jiangsu Food and Pharmaceuticals Science College, Institute of Food and Pharmaceuticals Research, 223005, People's Republic of China.
  • 7 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. Electronic address: hesiyu_cpu@163.com.
  • 8 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: pengyang@cpu.edu.cn.
  • 9 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China; School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China. Electronic address: fangpengfei@sioc.ac.cn.
  • 10 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. Electronic address: sunhaopeng@cpu.edu.cn.
PMID: 36566714 DOI: 10.1016/j.ejmech.2022.115013
Abstract

Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in multiple hormone related cancers, such as breast and prostate Cancer, and is correlated with tumor development and aggressiveness. As a phase I biotransformation Enzyme, AKR1C3 catalyzes the metabolic processes that lead to resistance to anthracyclines, the "gold standard" for breast Cancer treatment. Novel approaches to restore the chemotherapy sensitivity of breast Cancer are urgently required. Herein, we developed a new class of AKR1C3 inhibitors that demonstrated potent inhibitory activity and exquisite selectivity for closely related isoforms. The best derivative 27 (S19-1035) exhibits an IC50 value of 3.04 nM for AKR1C3 and >3289-fold selectivity over other isoforms. We determined the co-crystal structures of AKR1C3 with three of the inhibitors, providing a solid foundation for further structure-based drug optimization. Co-administration of these AKR1C3 inhibitors significantly reversed the doxorubicin (DOX) resistance in a resistant breast Cancer cell line. Therefore, the novel AKR1C3 specific inhibitors developed in this work may serve as effective adjuvants to overcome DOX resistance in breast Cancer treatment.

Keywords

AKR1C3; Breast cancer; Clinical drug resistance; Selective AKR1C3 inhibitors.

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