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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

Authors :
Kenneth V. Lawson
Jenna L. Jeffrey
Jay P. Powers
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.

Details

ISSN :
15204804
Volume :
63
Issue :
22
Database :
OpenAIRE
Journal :
Journal of medicinal chemistry
Accession number :
edsair.doi.dedup.....0c6d695fef9e6b1a7341abf8389d4b35