7wqr

Crystal structure of Aldo-keto reductase 1C3 complexed with compound 28

spinqualitylabelsall models 7wqr, resolution 2.12Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7wqr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.124Å Ligands: 4R6, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AK1C3_HUMAN Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone. Publication Abstract from PubMed 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 IC(50) 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. Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer.,Liu Y, Chen Y, Jiang J, Chu X, Guo Q, Zhao L, Feng F, Liu W, Zhang X, He S, Yang P, Fang P, Sun H Eur J Med Chem. 2023 Feb 5;247:115013. doi: 10.1016/j.ejmech.2022.115013. Epub , 2022 Dec 13. PMID:36566714 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Prostaglandin F synthase 3D structures

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