7WQM

Crystal structure of Aldo-keto reductase 1C3 complexed with compound 24

Summary for 7WQM

• Entry DOI: 10.2210/pdb7wqm/pdb
• Descriptor: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]-~{N}-(2-methoxyphenyl)benzamide, ... (4 entities in total)
• Functional Keywords: aldo-keto reductase, lipid metabolism, nad, nadp, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 77661.80

Authors

Jiang, J.,Liu, Y.,He, S.,Chen, Y.,Chu, X.,Liu, Y.,Guo, Q.,Zhao, L.,Feng, F.,Liu, W.,Zhang, X.,Sun, H.,Fang, P. (deposition date: 2022-01-25, release date: 2023-01-04, Last modification date: 2023-11-29)

Primary citation

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.
Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer.
Eur.J.Med.Chem., 247:115013-115013, 2022

PubMed Abstract: 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 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.

PubMed: 36566714
DOI: 10.1016/j.ejmech.2022.115013

Experimental method

X-RAY DIFFRACTION (2.13 Å)