A2AR antagonist EXS21546

An orally bioavailable immune checkpoint inhibitor and antagonist of the adenosine A2A receptor (A2AR; ADORA2A), with potential immunomodulating and antineoplastic activities. Upon oral administration, A2AR antagonist EXS21546 selectively targets, binds to and inhibits A2AR expressed on T-lymphocytes. This prevents tumor-released adenosine from interacting with the A2A receptors, thereby blocking the adenosine/A2AR-mediated inhibition of T-lymphocytes. This results in the proliferation and activation of T-lymphocytes, and stimulates a T-cell-mediated immune response against tumor cells. A2AR, a G protein-coupled receptor, is highly expressed on the cell surfaces of T-cells and, upon activation by adenosine, inhibits their proliferation and activation. Adenosine is often overproduced by cancer cells and plays a key role in immunosuppression in the tumor microenvironment (TME). EXS21546 does not penetrate the central nervous system (CNS).