4DBW

Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 2'-desmethyl-indomethacin

4DBW の概要

• エントリーDOI: 10.2210/pdb4dbw/pdb
• 分子名称: Aldo-keto reductase family 1 member C3, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, [1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid, ... (4 entities in total)
• 機能のキーワード: castrate resistant prostate cancer, akr1c3 selective inhibitor, tim barrel, steroid metabolism, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P42330
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76654.28

構造登録者

Chen, M.,Christianson, D.W.,Marnett, L.J.,Penning, T.M. (登録日: 2012-01-16, 公開日: 2013-03-06, 最終更新日: 2023-09-13)

主引用文献

Liedtke, A.J.,Adeniji, A.O.,Chen, M.,Byrns, M.C.,Jin, Y.,Christianson, D.W.,Marnett, L.J.,Penning, T.M.
Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17 beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.
J.Med.Chem., 56:2429-2446, 2013

PubMed Abstract: Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5α-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3·NADP(+)·2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.

PubMed: 23432095
DOI: 10.1021/jm3017656

実験手法

X-RAY DIFFRACTION (1.802 Å)