Novel CD73 Inhibitors for Treating Cancer

Abstract

The glycosyl-phosphatidylinositol (GPI)-anchored CD73 antigen (also known as Cluster of Differentiation 73, ecto-5′nucleotidase, ecto-5′-NT, 5′-NT, and NT5E) is considered the ratelimiting enzyme in the generation of extracellular adenosine. CD73 is a 70-kDa GPI-anchored protein normally expressed on endothelial cells and subsets of hematopoietic cells. CD73, together with CD39, regulates adenosine triphosphate (ATP) metabolism. CD39 converts ATP into AMP, with only trace amounts of ADP being released, while CD73 catalyzes the conversion of AMP to adenosine (Ado).Extracellular Ado accumulates in cancerous tissues and constitutes an important mechanism of tumor immune escape. CD73 can be found constitutively expressed at high levels on various types of cancer cells. CD73-generated adenosine is assumed to suppress adaptive antitumor immune responses, thereby promoting tumor growth and metastasis. The studies in animal models have shown that blockade of CD73 activity suppresses tumor growth and prolongs survival by promoting antitumor adaptive immunity.The present application describes a series of novel CD73 inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.