Abstract 1037: Orally available small molecule CD73 inhibitor reverses immunosuppression through blocking of adenosine production

Abstract

Abstract CD73 has emerged as an attractive target for cancer immunotherapy. CD73 (ecto-5-nucleotidase) is a glycosyl phosphatidyl inositol (GPI)-anchored cell surface protein and catalyzes the hydrolysis of AMP into immunosuppressive adenosine and inorganic phosphate. CD73 is widely overexpressed in tumor microenvironments (TME) of many cancers, resulting in elevated levels of extra cellular adenosine (ADO). ADO plays a critical role in tumor progression through immune suppression, chemotherapy resistance, metastasis and angiogenesis. Therefore, reducing the level of adenosine via inhibition of CD73 has become a potential strategy for treating cancers. Here we report our medicinal chemistry efforts in developing orally available small molecule CD73 inhibitors. Based on the binding mode of adenosine 5'-(α,β-methylene)diphosphate (APCP) with CD73, we designed a novel series of monophosphate CD73 inhibitors, which are highly potent and orally bioavailable. In preclinical studies, OP-5244 inhibited ADO production completely in human cancer cells and CD8+ T cells. It also showed dose-dependent inhibitory effects on CD73 activity in various tumors ex vivo. Furthermore, OP-5244 showed PK/PD efficacy through lowering of ADO/AMP ratio and reversal of immunosuppression in vivo. Citation Format: Xiaohui Du, Brian Blank, Brenda Chan, Xi Chen, Yuping Chen, Frank Duong, Lori Friedman, Tom Huang, Melissa R. Junttila, Wayne Kong, Todd Metzger, Jared Moore, Daqing Sun, Jessica Sun, Dena Sutimantanapi, Natalie Yuen, Tatiana Zavorotinskaya. Orally available small molecule CD73 inhibitor reverses immunosuppression through blocking of adenosine production [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1037.