ArticleBiochemical pharmacology2008
An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies.
Article in Biochemical pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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74 citing papers in PubMed, 137 citations in OpenAlex.
- AKR1C3 inhibitors and exploiters for the treatment and therapeutic monitoring of cancer: a patent review (2020-present).Expert opinion on therapeutic patents · 2026Review
- Article
- Role of Aldo-Keto reductase family 1 member C in cancer progression: a special focus on the role of AKR1C1 in pancreatic cancer.Medical oncology (Northwood, London, England) · 2025Article
- The structural basis of aldo-keto reductase 1C3 inhibition by 17α-picolyl and 17(Journal of enzyme inhibition and medicinal chemistry · 2025Article
- Bioactivity profiling ofJournal of enzyme inhibition and medicinal chemistry · 2025Article
- Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1,8-Dinitropyrene and Its Metabolite 1-Amino-8-nitropyrene via Nitroreduction in Human Lung Cells.Chemical research in toxicology · 2025Article
- Discovery and Optimization of a Covalent AKR1C3 Inhibitor.Journal of medicinal chemistry · 2025Article
- Article
- AKR1C3 mediates gastric cancer cell invasion and metastasis via the AKT and JNK/p-NF-κB signaling pathways.Scientific reports · 2024Article
- Analysis of Expression and Regulation of AKR1C2 in HPV-Positive and -Negative Oropharyngeal Squamous Cell Carcinoma.Cancers · 2024Article
- Aldo-keto reductases: Role in cancer development and theranostics.Oncology research · 2024Review
- AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies.Frontiers in pharmacology · 2024Review
- X-ray structure of human aldo-keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation, molecular docking and structural analysis.RSC medicinal chemistry · 2023Article
- Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1-Nitropyrene via Nitroreduction in Human Lung Cells.Chemical research in toxicology · 2023Article
- Steroid 5β-reductase (AKR1D1): Purification and characterization.Methods in enzymology · 2023Article
- Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes.Endocrinology · 2022Article
- Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3.Metabolites · 2022Article
- Interactions between exposure to polycyclic aromatic hydrocarbons and xenobiotic metabolism genes, and risk of breast cancer.Breast cancer (Tokyo, Japan) · 2022Article
- Protocadherin 19 Clustering Epilepsy and Neurosteroids: Opportunities for Intervention.International journal of molecular sciences · 2021Review
- Aldo-Keto Reductases and Cancer Drug Resistance.Pharmacological reviews · 2021Review
14 more citing papers are in PubMed but not listed here.
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3 authors at 1 institution in 1 country.
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Abstract
Aldo-keto reductase (AKR) 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase) regulates ligand access to steroid hormone and prostaglandin receptors and may stimulate proliferation of prostate and breast cancer cells. NSAIDs are known inhibitors of AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C family members would provide an important tool to examine the role of AKR1C3 in proliferative signaling. We tested NSAIDs and NSAID analogues for inhibition of the reduction of 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoforms AKR1C1 and AKR1C2. Two of the compounds initially screened, indomethacin and its methyl ester, were specific for AKR1C3 versus the other AKR1C isoforms. Based on these results and the crystal structure of AKR1C3, we predicted that N-(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction of PQ by AKR1C3, but did not significantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction of Delta(4)-androstene-3,17-dione but did not significantly inhibit the reduction of steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern of inhibition of AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Delta(4)-androstene-3,17-dione, indicating that two different inhibitory complexes form during the ordered bi bi reactions. The identification of CBM as a specific inhibitor of AKR1C3 will aid the investigation of its roles in steroid hormone and prostaglandin signaling and the resultant effects on cancer development.
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