6FXH

Human cytosolic 5'-nucleotidase II soaked with 10mM 3-Phenyl-N-(9H-purin-6-yl)benzamide

6FXH の概要

• エントリーDOI: 10.2210/pdb6fxh/pdb
• 関連するPDBエントリー: 2J2C 4H4B 5CQZ 5CR7 6FIR 6FIS 6FIU 6FIW
• 分子名称: Cytosolic purine 5'-nucleotidase, SULFATE ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 65951.99

構造登録者

Aghajari, N.,Preeti, P. (登録日: 2018-03-09, 公開日: 2019-03-06, 最終更新日: 2024-01-17)

主引用文献

Guillon, R.,Rahimova, R.,Egron, D.,Rouanet, S.,Dumontet, C.,Aghajari, N.,Jordheim, L.P.,Chaloin, L.,Peyrottes, S.
Lead optimization and biological evaluation of fragment-based cN-II inhibitors.
Eur J Med Chem, 168:28-44, 2019

PubMed Abstract: The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200 μM and among them three derivatives (12, 13 and 18) exhibited K in the sub-millimolar range (0.84, 2.4 and 0.58 mM, respectively). Despite their only modest potency, the cN-II inhibitors showed synergistic effects when used in combination with cytotoxic purine nucleoside analogues on cancer cells. Therefore, these derivatives represent a family of non-nucleos(t)idic cN-II inhibitors with potential usefulness to overcome cancer drug resistance especially in hematological malignancies in which cN-II activity has been described as an important parameter.

PubMed: 30798051
DOI: 10.1016/j.ejmech.2019.02.040

実験手法

X-RAY DIFFRACTION (2.3 Å)