ArticlePLoS computational biology2018
Identification of allosteric inhibitors of the ecto-5'-nucleotidase (CD73) targeting the dimer interface.
Article in PLoS computational biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Third-Generation CD73 Inhibitors Based on a 4,6-Disubstituted-2-Thiopyridine Scaffold.ChemMedChem · 2025Article
- Anti-inflammatory potency of novel ecto-5'-nucleotidase/CD73 inhibitors in astrocyte culture model of neuroinflammation.European journal of pharmacology · 2023Article
- The Clinical Significance of CD73 in Cancer.International journal of molecular sciences · 2023Review
- A Novel Anti-CD73 Antibody That Selectively Inhibits Membrane CD73 Shows Antitumor Activity and Induces Tumor Immune Escape.Biomedicines · 2022Article
- Transcriptional and Metabolic Investigation in 5'-Nucleotidase Deficient Cancer Cell Lines.Cells · 2021Article
- CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer.Scientific reports · 2021Article
- Anti-Inflammatory Effects of Quercetin on High-Glucose and Pro-Inflammatory Cytokine Challenged Vascular Endothelial Cell Metabolism.Molecular nutrition & food research · 2021Article
- Enhanced migration of breast and lung cancer cells deficient for cN-II and CD73 via COX-2/PGE2/AKT axis regulation.Cellular oncology (Dordrecht, Netherlands) · 2021Article
- Leukocyte Membrane Enzymes Play the Cell Adhesion Game.Frontiers in immunology · 2021Review
- Article
- Extracellular NADScientific reports · 2020Article
- Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Targets.Frontiers in molecular biosciences · 2020Article
- Be Aware of Aggregators in the Search for Potential HumanMolecules (Basel, Switzerland) · 2018Article
- Article
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ecto-5'-nucleotidase CD73 plays an important role in the production of immune-suppressive adenosine in tumor micro-environment, and has become a validated drug target in oncology. Indeed, the anticancer immune response involves extracellular ATP to block cell proliferation through T-cell activation. However, in the tumor micro-environment, two extracellular membrane-bound enzymes (CD39 and CD73) are overexpressed and hydrolyze efficiently ATP into AMP then further into immune-suppressive adenosine. To circumvent the impact of CD73-generated adenosine, we applied an original bioinformatics approach to identify new allosteric inhibitors targeting the dimerization interface of CD73, which should impair the large dynamic motions required for its enzymatic function. Several hit compounds issued from virtual screening campaigns showed a potent inhibition of recombinant CD73 with inhibition constants in the low micromolar range and exhibited a non-competitive inhibition mode. The structure-activity relationships studies indicated that several amino acid residues (D366, H456, K471, Y484 and E543 for polar interactions and G453-454, I455, H456, L475, V542 and G544 for hydrophobic contacts) located at the dimerization interface are involved in the tight binding of hit compounds and likely contributed for their inhibitory activity. Overall, the gathered information will guide the upcoming lead optimization phase that may lead to potent and selective CD73 inhibitors, able to restore the anticancer immune response.
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