Design, Synthesis, and Bioevaluation of 2-Aminopteridin-7(8 H )-one Derivatives as Novel Potent Adenosine A 2A Receptor Antagonists for Cancer Immunotherapy.

In recent years, the adenosine A 2A receptor (A 2A R) has shown exciting progress in the development of immunotherapies for the treatment of cancer. Herein, a 2-amino-7,9-dihydro-8 H -purin-8-one compound ( 1 ) was identified as an A 2A R antagonist hit through in-house library screening. Extensive structure-activity relationship (SAR) studies led to the discovery of 2-aminopteridin-7(8 H )-one derivatives, which showed high potencies on A 2A R in the cAMP assay. Compound 57 stood out with an IC 50 value of 8.3 ± 0.4 nM against A 2A R at the 5'- N -ethylcarboxamidoadenosine (NECA) level of 40 nM. The antagonistic effect of 57 was sustained even at a higher NECA concentration of 1 μM, which mimicked the adenosine level in the tumor microenvironment (TME). Importantly, 57 enhanced T cell activation in both the IL-2 production assay and the cancer-cell-killing model, thus demonstrating its potential as a lead for developing novel A 2A R antagonists in cancer immunotherapy.