7JV8

Human CD73 (ecto 5'-nucleotidase) in complex with compound 35

7JV8 の概要

• エントリーDOI: 10.2210/pdb7jv8/pdb
• 分子名称: 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: 5'-nucleotidase, hydrolase, phosphatase, proteros, proteros biostructures gmbh, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 237898.68

構造登録者

Gibbons, P.,Du, X. (登録日: 2020-08-20, 公開日: 2020-09-23, 最終更新日: 2024-11-13)

主引用文献

Du, X.,Moore, J.,Blank, B.R.,Eksterowicz, J.,Sutimantanapi, D.,Yuen, N.,Metzger, T.,Chan, B.,Huang, T.,Chen, X.,Chen, Y.,Duong, F.,Kong, W.,Chang, J.H.,Sun, J.,Zavorotinskaya, T.,Ye, Q.,Junttila, M.R.,Ndubaku, C.,Friedman, L.S.,Fantin, V.R.,Sun, D.
Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production.
J.Med.Chem., 63:10433-10459, 2020

PubMed Abstract: The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5'-(α,β-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 () proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, completely inhibited ADO production in both human cancer cells and CD8 T cells. Furthermore, lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an tool compound for further development.

PubMed: 32865411
DOI: 10.1021/acs.jmedchem.0c01086

実験手法

X-RAY DIFFRACTION (2.46 Å)