CD73 (ecto-5-nucleotidase) is a key enzyme in the adenosinergic pathway 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, which may play a critical role in tumor progression through various mechanisms such as immune suppression, chemotherapy resistance, metastasis and angiogenesis. Reducing the level of adenosine via inhibition of CD73 has become a much sought-after 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’-(a,b-methylene)diphosphate (AOPCP) with CD73, we designed novel scaffolds of monophosphate CD73 inhibitors, which are highly potent and orally bioavailable. In preclinical studies, OP-5244 showed dose-dependent inhibitory effects on CD73 activity in various tumors through histochemical analysis. It also rescued AMP-suppressed CD8+ T-cell proliferation as well as cytokine (IFNg and TNFa) production. Furthermore, OP-5244 blocked CD73-mediated production of adenosine in the TME <i>in vivo</i>.

Orally bioavailable small molecule CD73 inhibitor reverses immunosuppression by reduction of adenosine production

ACS Fall 2020 Virtual Meeting

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