2. Academic Validation
  3. Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment

Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment

  • J Med Chem. 2023 Jul 6. doi: 10.1021/acs.jmedchem.3c00213.
Siyu He 1 2,  Xianglin Chu 1,  Yujia Wu 3,  Jiheng Jiang 4 5,  Pengfei Fang 4 5,  Yuting Chen 1,  Yang Liu 1,  Zhixia Qiu 6,  Yibei Xiao 6 7 8,  Zhiyu Li 1 6,  Di Pan 9,  Qian Zhang 6 7 8,  Huanfang Xie 1,  Shuaishuai Xing 1,  Feng Feng 10 11,  Wenyuan Liu 1,  Qinglong Guo 3,  Li Zhao 3,  Peng Yang 1 6,  Haopeng Sun 1
Affiliations

Affiliations

  • 1 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
  • 2 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China.
  • 3 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.
  • 4 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 5 State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
  • 6 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 7 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 8 Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 4015, China.
  • 9 The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou, China.
  • 10 School of Pharmacy, Nanjing Medical University, 211166 Nanjing, People's Republic of China.
  • 11 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
PMID: 37409679 DOI: 10.1021/acs.jmedchem.3c00213
Abstract

Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the Enzyme has been recognized as one of the important factors in inducing anthracycline (ANT) resistance in Cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue S07-1066 selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of S07-1066 significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in Cancer treatment.

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