Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production

The
adenosinergic pathway represents an attractive new therapeutic
approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase
CD73 has the unique function of regulating production of immunosuppressive
adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed
in many cancers, resulting in elevated levels of ADO that correspond
to poor patient prognosis. Therefore, reducing the level of ADO via
inhibition of CD73 is a potential strategy for treating cancers. Based
on the binding mode of adenosine 5′-(α,β-methylene)­diphosphate
(AOPCP) with human CD73, we designed a series of novel monophosphonate
small-molecule CD73 inhibitors. Among them, OP-5244 (35) proved to be a highly potent and orally bioavailable CD73 inhibitor.
In preclinical studies, 35 completely inhibited ADO production
in both human cancer cells and CD8+ T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed
immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.