7C7F

Crystal structures of AKR1C3 binary complex with NADP+

7C7F の概要

• エントリーDOI: 10.2210/pdb7c7f/pdb
• 分子名称: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: cancer, 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: 75953.89

構造登録者

Irie, K.,Toyooka, N.,Endo, S. (登録日: 2020-05-25, 公開日: 2020-09-23, 最終更新日: 2023-11-29)

主引用文献

Endo, S.,Oguri, H.,Segawa, J.,Kawai, M.,Hu, D.,Xia, S.,Okada, T.,Irie, K.,Fujii, S.,Gouda, H.,Iguchi, K.,Matsukawa, T.,Fujimoto, N.,Nakayama, T.,Toyooka, N.,Matsunaga, T.,Ikari, A.
Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer.
J.Med.Chem., 63:10396-10411, 2020

PubMed Abstract: Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, -(4-fluorophenyl)-8-hydroxy-2-imino-2-chromene-3-carboxamide (), and synthesized its derivatives with IC values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with and . The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, and prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).

PubMed: 32847363
DOI: 10.1021/acs.jmedchem.0c00939

実験手法

X-RAY DIFFRACTION (1.7 Å)