Discovery of a Series of Potent, Selective, and Orally Bioavailable Nucleoside Inhibitors of CD73 That Demonstrates In Vivo Antitumor Activity
- J Med Chem. 2022 Dec 18. doi: 10.1021/acs.jmedchem.2c01287.
- 1. Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States.
- 2. Wuxi AppTec, Shanghai 200131, China.
- 3. NEDP, Branford, Connecticut 06405, United States.
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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