The CD73, also known as ecto-5'-nucleotidase (NT5E), is a cell surface enzyme overexpressed on tumor cells. The CD73 catalyzes the conversion of AMP to ADO. In the tumor microenvironment (TME), binding of extracellular ADO to adenosine receptors (AR) promotes the proliferation of immunosuppressive cells and inhibits the cytotoxic immune response which diminishes the immune response towards cancer cells. Recently, antibody blockade of CD73 is shown to increase the therapeutic efficacy of clinically approved immunotherapies in preclinical models. This suggests the benefits of developing small molecular anti-CD73 inhibitor to enhance immunity or combination with immune checkpoint blockade immunotherapy. Here we have synthesized, characterized and evaluated a novel series of ecto-5'-nucleotidase inhibitors. The most potent compound was shown with IC50 values of 0.3 μM (APCP as 2.5 μM) on recombinant protein. The competition assay was implemented to explain the non-competitive inhibition mechanism.

Development of novel ecto-5'-nucleotidase inhibitor with non-competitive mechanism

2019 Fall National Meeting

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