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Targeting Metabolism of Extracellular Nucleotides via Inhibition of Ectonucleotidases CD73 and CD39
Targeting Metabolism of Extracellular Nucleotides via Inhibition of Ectonucleotidases CD73 and CD39
- Source :
- Journal of medicinal chemistry. 63(22)
- Publication Year :
- 2020
-
Abstract
- In the tumor microenvironment, unusually high concentrations of extracellular adenosine promote tumor proliferation through various immunosuppressive mechanisms. Blocking adenosine production by inhibiting nucleotide-metabolizing enzymes, such as ectonucleotidases CD73 and CD39, represents a promising therapeutic strategy that may synergize with other immuno-oncology mechanisms and chemotherapies. Emerging small-molecule ectonucleotidase inhibitors have recently entered clinical trials. This Perspective will outline challenges, strategies, and recent advancements in targeting this class with small-molecule inhibitors, including AB680, the first small-molecule CD73 inhibitor to enter clinical development. Specific case studies, including structure-based drug design and lead optimization, will be outlined. Preclinical data on these molecules and their ability to enhance antitumor immunity will be discussed.
- Subjects :
- Drug
media_common.quotation_subject
Antineoplastic Agents
GPI-Linked Proteins
01 natural sciences
Protein Structure, Secondary
03 medical and health sciences
Drug Delivery Systems
Drug Discovery
medicine
Extracellular
Humans
Ectonucleotidase
Nucleotide
Enzyme Inhibitors
5'-Nucleotidase
030304 developmental biology
media_common
chemistry.chemical_classification
0303 health sciences
Tumor microenvironment
Nucleotides
Apyrase
Metabolism
Adenosine
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Enzyme
chemistry
Cancer research
Molecular Medicine
medicine.drug
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 63
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....0c6d695fef9e6b1a7341abf8389d4b35