CD73
(ecto-5′-nucleotidase) has emerged as an attractive
target for cancer immunotherapy of many cancers. CD73 catalyzes the
hydrolysis of adenosine monophosphate (AMP) into highly immunosuppressive
adenosine that plays a critical role in tumor progression. Herein,
we report our efforts in developing orally bioavailable and highly
potent small-molecule CD73 inhibitors from the reported hit molecule 2 to lead molecule 20 and then finally to compound 49. Compound 49 was able to reverse AMP-mediated
suppression of CD8+ T cells and completely inhibited CD73
activity in serum samples from various cancer patients. In preclinical in vivo studies, orally administered 49 showed
a robust dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship
that correlated with efficacy. Compound 49 also demonstrated
the expected immune-mediated antitumor mechanism of action and was
efficacious upon oral administration not only as a single agent but
also in combination with either chemotherapeutics or checkpoint inhibitor
in the mouse tumor model.
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