2. Academic Validation
  3. Design, Synthesis, and Bioevaluation of 2-Aminopteridin-7(8 H)-one Derivatives as Novel Potent Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

Design, Synthesis, and Bioevaluation of 2-Aminopteridin-7(8 H)-one Derivatives as Novel Potent Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

  • J Med Chem. 2022 Mar 10;65(5):4367-4386. doi: 10.1021/acs.jmedchem.1c02199.
Fazhi Yu 1,  Chenyu Zhu 1,  Shuyin Ze 2,  Haojie Wang 1,  Xinyu Yang 2,  Mingyao Liu 2,  Qiong Xie 1 3,  Weiqiang Lu 2,  Yonghui Wang 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
  • 3 Fudan Zhangjiang Institute, 666 Zhangheng Road, Shanghai 201203, China.
PMID: 35212542 DOI: 10.1021/acs.jmedchem.1c02199
Abstract

In recent years, the adenosine A2A receptor (A2AR) 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 A2AR antagonist hit through in-house library screening. Extensive structure-activity relationship (SAR) studies led to the discovery of 2-aminopteridin-7(8H)-one derivatives, which showed high potencies on A2AR in the cAMP assay. Compound 57 stood out with an IC50 value of 8.3 ± 0.4 nM against A2AR 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 A2AR antagonists in Cancer Immunotherapy.

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