Discovery of a Series of Potent, Selective, and Orally Bioavailable Nucleoside Inhibitors of CD73 That Demonstrates In Vivo Antitumor Activity

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.

Automated summary

CD73 is an attractive target for cancer immunotherapy due to its involvement in the production of immunosuppressive adenosine. In this study, small molecules were developed as potent and orally bioavailable CD73 inhibitors, with compound 49 showing promising results in reversing CD73-mediated immune suppression and inhibiting CD73 activity in cancer patient samples. Additionally, compound 49 exhibited efficacious anti-tumor activity both as a single agent and in combination with chemotherapeutics or checkpoint inhibitors in preclinical mouse models.