6XUG

Human Ecto-5'-nucleotidase (CD73) in complex with A2410 (compound 53 in publication) in the closed form in crystal form IV

6XUG の概要

• エントリーDOI: 10.2210/pdb6xug/pdb
• 分子名称: 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: non-nucleotide inhibitor, hydrolase, arcus biosciences
• 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: 120272.43

構造登録者

Strater, N. (登録日: 2020-01-19, 公開日: 2020-04-22, 最終更新日: 2024-11-06)

主引用文献

Beatty, J.W.,Lindsey, E.A.,Thomas-Tran, R.,Debien, L.,Mandal, D.,Jeffrey, J.L.,Tran, A.T.,Fournier, J.,Jacob, S.D.,Yan, X.,Drew, S.L.,Ginn, E.,Chen, A.,Pham, A.T.,Zhao, S.,Jin, L.,Young, S.W.,Walker, N.P.,Leleti, M.R.,Moschutz, S.,Strater, N.,Powers, J.P.,Lawson, K.V.
Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73.
J.Med.Chem., 63:3935-3955, 2020

PubMed Abstract: CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2-indazol-6-yl)-1-1,2,3-benzotriazol-6-yl]-1-pyrazol-1-yl}methyl)benzonitrile (, IC = 12 nM) and 4-({5-[4-chloro-1-(2-indazol-6-yl)-1-1,2,3-benzotriazol-6-yl]-1-pyrazol-1-yl}methyl)benzonitrile (, IC = 19 nM). Cocrystallization of with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.

PubMed: 32212732
DOI: 10.1021/acs.jmedchem.9b01713

実験手法

X-RAY DIFFRACTION (2.09 Å)