3ARN

Human dUTPase in complex with novel uracil derivative

3ARN の概要

• エントリーDOI: 10.2210/pdb3arn/pdb
• 関連するPDBエントリー: 2HQU 3ARA
• 分子名称: Deoxyuridine 5'-triphosphate nucleotidohydrolase, N-{5-[(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy]-2-methylpentan-2-yl}benzenesulfonamide, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform 2: Nucleus . Isoform 3: Mitochondrion : P33316
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 54603.38

構造登録者

Chong, K.T.,Miyahara, S.,Miyakoshi, H.,Fukuoka, M. (登録日: 2010-12-03, 公開日: 2010-12-15, 最終更新日: 2024-03-13)

主引用文献

Miyahara, S.,Miyakoshi, H.,Yokogawa, T.,Chong, K.T.,Taguchi, J.,Muto, T.,Endoh, K.,Yano, W.,Wakasa, T.,Ueno, H.,Takao, Y.,Fujioka, A.,Hashimoto, A.,Itou, K.,Yamamura, K.,Nomura, M.,Nagasawa, H.,Shuto, S.,Fukuoka, M.
Discovery of a novel class of potent human deoxyuridine triphosphatase inhibitors remarkably enhancing the antitumor activity of thymidylate synthase inhibitors
J.Med.Chem., 55:2970-2980, 2012

PubMed Abstract: Inhibition of human deoxyuridine triphosphatase (dUTPase) has been identified as a promising approach to enhance the efficacy of 5-fluorouracil (5-FU)-based chemotherapy. This study describes the development of a novel class of dUTPase inhibitors based on the structure-activity relationship (SAR) studies of uracil derivatives. Starting from the weak inhibitor 7 (IC(50) = 100 μM), we developed compound 26, which is the most potent human dUTPase inhibitor (IC(50) = 0.021 μM) reported to date. Not only does compound 26 significantly enhance the growth inhibition activity of 5-fluoro-2'-deoxyuridine (FdUrd) against HeLa S3 cells in vitro (EC(50) = 0.075 μM) but also shows robust antitumor activity against MX-1 breast cancer xenograft model in mice when administered orally with a continuous infusion of 5-FU. This is the first in vivo evidence that human dUTPase inhibitors enhance the antitumor activity of TS inhibitors. On the basis of these findings, it was concluded that compound 26 is a promising candidate for clinical development.

PubMed: 22339362
DOI: 10.1021/jm201628y

実験手法

X-RAY DIFFRACTION (1.8 Å)