Discovery of Novel Non-Nucleoside Inhibitors Interacting with Dizinc Ions of CD73

High extracellular concentrations of adenosine triphosphate
(ATP)
in the tumor microenvironment generate adenosine by sequential dephosphorylation
of CD39 and CD73, resulting in potent immunosuppression to inhibit
T cell and natural killer (NK) cell function. CD73, as the determining
enzyme for adenosine production, has been shown to correlate with
poor clinical tumor prognosis. Conventional inhibitors as analogues
of adenosine 5′-monophosphate (AMP) may have a risk of further
metabolism to adenosine analogues. Here, we report a new series of
malonic acid non-nucleoside inhibitors coordinating with zinc ions
of CD73. Compound 12f was found to be a superior CD73
inhibitor (IC50 = 60 nM) by structural optimization, and
its pharmacokinetic properties were investigated. In mouse tumor models,
compound 12f showed excellent efficacy and reversal of
immunosuppression in combination with chemotherapeutic agents or checkpoint
inhibitors, suggesting that it deserves further development as a novel
CD73 inhibitor.