Emerging small-molecule AKR1C3 inhibitors development for cancer therapy: Progress from 2021 to 2025
Hao-Nan Gao1, Xing-Sen Wu1, Zhi-Jun Pan1
1Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, School of Pharmacy, Wannan Medical College, Wuhu, 241000, PR China.
European Journal of Medicinal Chemistry
|December 25, 2025
Summary
Aldehyde Ketone Reductase 1C3 (AKR1C3) drives cancer growth by altering hormone activity. Inhibitor development shows promise for treating cancers like prostate and breast cancer.
Area of Science:
- Biochemistry
- Enzymology
- Cancer Biology
Background:
- Aldehyde Ketone Reductase 1C3 (AKR1C3), also known as 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) or prostaglandin F (PGF) synthase, regulates hormone activity and PGF synthesis.
- AKR1C3 catalyzes the conversion of hormone precursors to active forms, influencing cellular proliferation and differentiation.
- Aberrant AKR1C3 overexpression is linked to tumor recurrence and therapy resistance in prostate and breast cancers, promoting malignant phenotypes.
Purpose of the Study:
- To provide a comprehensive overview of the AKR1C enzyme family, focusing on AKR1C3.
- To highlight AKR1C3's role in tumor-promoting pathways.
- To summarize recent advances (2021-2025) in the discovery and optimization of AKR1C3 inhibitors.
Main Methods:
- Review of structural and functional attributes of AKR1C3.
- Analysis of AKR1C3's mechanistic involvement in cancer.
- Systematic summary of medicinal chemistry strategies, SAR trends, and translational potential of AKR1C3 inhibitors.
Main Results:
- AKR1C3's critical role in regulating active steroids and prostaglandins, contributing to cancer progression.
- Significant progress in developing potent and selective small-molecule AKR1C3 inhibitors.
- Identification of key medicinal chemistry strategies and SAR trends for inhibitor optimization.
Conclusions:
- AKR1C3 is a validated therapeutic target for cancers, particularly prostate and breast cancer.
- Recent inhibitor development shows translational potential for clinical application.
- Continued research into AKR1C3 inhibitors is crucial for advancing cancer therapy.
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