2. Academic Validation
  3. Subtle Structural Changes across the Boundary between A2AR/A2BR Dual Antagonism and A2BR Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives

Subtle Structural Changes across the Boundary between A2AR/A2BR Dual Antagonism and A2BR Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives

  • J Med Chem. 2024 Mar 28;67(6):5075-5092. doi: 10.1021/acs.jmedchem.4c00250.
Haojie Wang 1,  Xinyu Yang 2,  Yan Li 1,  Shuyin Ze 3,  Bo Feng 4,  Yuan Weng 3,  Aoqi Gao 3,  Gaojie Song 3,  Mingyao Liu 3 5,  Qiong Xie 1,  Yonghui Wang 1,  Weiqiang Lu 2
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, School of Life Sciences, Shanghai Key Laboratory of Multidimensional Information Processing, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
  • 4 Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5 Shanghai Yuyao Biotech Co., Ltd., Shanghai 200041, China.
PMID: 38483150 DOI: 10.1021/acs.jmedchem.4c00250
Abstract

Aberrantly elevated adenosine in the tumor microenvironment exerts its immunosuppressive functions through adenosine receptors A2AR and A2BR. Antagonism of A2AR and A2BR has the potential to suppress tumor growth. Herein, we report a systemic assessment of the effects of an indole modification at position 4, 5, 6, or 7 on both A2AR/A2BR activity and selectivity of novel 2-aminopyrimidine compounds. Substituting indole at the 4-/5-position produced potent A2AR/A2BR dual antagonism, whereas the 6-position of indole substitution gave highly selective A2BR antagonism. Molecular dynamics simulation showed that the 5-cyano compound 7ai had a lower binding free energy than the 6-cyano compound 7aj due to water-bridged hydrogen bond interactions with E169 or F168 in A2AR. Of note, dual A2AR/A2BR antagonism by compound 7ai can profoundly promote the activation and cytotoxic function of T cells. This work provided a strategy for obtaining novel dual A2AR/A2BR or A2BR antagonists by fine-tuning structural modification.

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