Medicinal Chemistry of Purinergic Signaling: Development of Ectonucleotidase Inhibitors for Cancer Immunotherapy

The extracellular nucleoside adenosine is an important signaling molecule activating G protein-coupled purine P1 (adenosine) receptors. These receptors, that belong to the family of class A, rhodopsin-like GPCRs, play crucial roles in inflammation, immunity, and cancer. For example, cancer and inflamed tissues can release large amounts of the nucleotide ATP, which is hydrolyzed by ectonucleotidases, expressed on many cancer and immune cells, leading to the production of high levels of extracellular adenosine. Subsequent activation of G protein-coupled adenosine A2A and A2B receptors results in cancer-promoting, angiogenic, pro-metastatic, and strongly immunosuppressive effects. Recent progress in the identification and optimization of ectonucleotidase inhibitors, utilizing structural biology, will be presented. These tool compounds, including labeled derivatives and conjugates, are used to study their targets’ role in health and disease. Moreover, they have potential for further development as diagnostic and therapeutic drugs.