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

作者：Fazhi Yu, Chenyu Zhu, Shuyin Ze, Haojie Wang, Xinyu Yang, Mingyao Liu, Qiong Xie, Weiqiang Lü, Yonghui Wang · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.1c02199 · 被引用次数：16 · 研究领域：Adenosine and Purinergic Signaling、RNA Interference and Gene Delivery、Calcium signaling and nucleotide metabolism

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.