2. Academic Validation
  3. Discovery of Highly Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma

Discovery of Highly Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma

  • J Med Chem. 2025 Apr 10;68(7):7367-7389. doi: 10.1021/acs.jmedchem.4c03035.
Shuaishuai Xing 1,  Jiheng Jiang 2,  Xianglin Chu 1,  Xiaolong Wang 1,  Zhiqiang Wang 3,  Xinyu Li 1,  Bingbing Lv 3,  Can Guo 1,  Siyu He 4,  Leyan Wang 1,  Chenyu Zhang 1,  Qinglong Guo 5 6,  Li Zhao 5,  Pengfei Fang 2 7,  Feng Feng 8,  Haopeng Sun 1
Affiliations

Affiliations

  • 1 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
  • 2 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou 310024, People's Republic of China.
  • 3 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China.
  • 4 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, People's Republic of China.
  • 5 Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, People's Republic of China.
  • 6 Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, Jiangsu, People's Republic of China.
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People's Republic of China.
  • 8 School of Pharmacy, Nanjing Medical University, 211166 Nanjing, People's Republic of China.
PMID: 40143712 DOI: 10.1021/acs.jmedchem.4c03035
Abstract

Aldo-keto reductase 1C3 (AKR1C3) plays a key role in tumor progression and chemotherapy resistance, particularly in sorafenib-resistant hepatocellular carcinoma (HCC). Targeting AKR1C3 represents a promising strategy to restore chemosensitivity in resistant HCC. Previous research identified the lead compound S07-2005 through a cascade virtual screening approach (AKR1C3 IC50 = 130 ± 30 nM, SI (selective index) > 77). Using cocrystal-guided drug design, 30 was optimized to adopt an "L"-shaped conformation targeting AKR1C3's subpocket 1 (SP1) and oxyanion site (OS), enhancing inhibitory potency and selectivity (AKR1C3 IC50 = 5 ± 1 nM, SI > 2000). It enhanced sorafenib-induced ROS generation, promoted Apoptosis, and restored sorafenib sensitivity in HCC models. In combination with sorafenib, compound 30 restored sorafenib sensitivity in HCC both in vitro and in vivo. Additionally, compound 30 demonstrated a favorable safety profile and pharmacokinetic properties, suggesting its potential as an adjunct to overcome AKR1C3-mediated chemotherapy resistance in Cancer treatment.

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