Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production
Xiaohui Du, Jared T. Moore, Brian R. Blank, John Eksterowicz, Dena Sutimantanapi, Natalie Yuen, Todd C. Metzger, Brenda Chan, Tom Huang, Xi Chen, Yuping Chen, Frank Duong, Wayne Kong, Jae H. Chang, Jessica D. Sun, Tatiana Zavorotinskaya, Qiuping Ye, Melissa R. Junttila, Chudi Ndubaku, Lori S. Friedman, Valeria R. Fantin, Daqing Sun
Abstract
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.