Jacobson, Kenneth (NIDDK)
Mueller, Christa (University of Bonn)
Junker, Anna (University of Munster)
These small molecules are novel nucleotide derivatives, containing either a purine or pyrimidine nucleobase, that competitively block the enzyme CD73, also known as ecto-5'-nucleotidase. This enzyme converts extracellular AMP (not a potent activator of adenosine receptors) to adenosine (the native activator of 4 subtypes of adenosine receptors. CD73 inhibitors are being used, in clinical trials and preclinical research, in conjunction with cancer immunotherapy. CD73 is upregulated around tumors to produce excessive adenosine, and blocking this enzyme greatly reduces immunosuppressive adenosine in the tumor microenvironment. Therefore, combined therapy is expected to be more effective than cancer immunotherapy alone. Pharma companies are working on blockers, either small molecules or monocolonal antibodies, to block CD73 for application to cancer therapy, and some have already entered clinical trials.
- Coadministration of an inhibitor of CD73 offers synergistic anti-tumor activity
- In addition to cancer immunotherapy, CD73 inhibitors might have utility in preeclampsia, pulmonary edema, infectious disease, and other conditions
- Previously, adenine nucleotides have been used as CD73 inhibitors in research, but these can lead to off-target activity at purinergic receptors. Thus, the ability to potently inhibit the enzyme using a different nucleobase derivative can provide greater specificity for the target in comparison to earlier inhibitors.