7WQS

Crystal structure of Aldo-keto reductase 1C3 complexed with compound 25

7WQS の概要

• エントリーDOI: 10.2210/pdb7wqs/pdb
• 分子名称: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 2-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]-~{N}-(3-methoxyphenyl)benzamide, ... (4 entities in total)
• 機能のキーワード: aldo-keto reductase, lipid metabolism, nad, nadp, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77661.80

構造登録者

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. (登録日: 2022-01-26, 公開日: 2023-01-04, 最終更新日: 2023-11-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.07 Å)