7JV8

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

Summary for 7JV8

• Entry DOI: 10.2210/pdb7jv8/pdb
• Descriptor: 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: 5'-nucleotidase, hydrolase, phosphatase, proteros, proteros biostructures gmbh, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 237898.68

Authors

Gibbons, P.,Du, X. (deposition date: 2020-08-20, release date: 2020-09-23, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.46 Å)