Design, Synthesis, and Bioevaluation of 2-Aminopteridin-7(8H)-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-8H-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-aminopteridin7(8H)-one derivatives, which showed high potencies on A(2A)R in the cAMP assay. Compound 57 stood out with an IC50 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 mu M, 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.