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.
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Article Synopsis
- The main enzymes responsible for breaking down nucleotides at the cell surface are NTPDases, ENPPs, alkaline phosphatases, and e5'NT, which can influence various health conditions like cancer and inflammation, making them potential therapeutic targets.
- This review focuses on ectonucleotidase inhibitors, including both nucleoside/nucleotide analogues and bicyclic compounds, that have been patented between 2017 and 2023, highlighting their chemistry and clinical applications.
- The review emphasizes the importance of nucleotides in regulating key physiological processes and discusses the therapeutic potential of small molecules that affect ectonucleotidase activity, including advancements in combination therapy and selectivity.
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