2. Academic Validation
  3. Chirality-Guided Optimization of A2A Adenosine Receptor Antagonists for Enhanced Metabolic Stability and Antitumor Efficacy

Chirality-Guided Optimization of A2A Adenosine Receptor Antagonists for Enhanced Metabolic Stability and Antitumor Efficacy

  • J Med Chem. 2025 Jul 24;68(14):14962-14980. doi: 10.1021/acs.jmedchem.5c01141.
Wen Ding 1 2,  Shuhao Liu 1 3 4 5,  Wenjiang Liu 1 3 4,  Zhijing Zhang 1 3 4,  Jingyu Zhao 1 3 4,  Xiaolei Zhang 1,  Taoda Shi 1 3 4,  Wenhao Hu 1 3 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China.
  • 3 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 4 Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, Sun Yat-Sen University, Guangzhou 510006, China.
  • 5 Division of Abdominal Tumor Multimodality Treatment and Laboratory of Cell Engineering and Immunotherapy, Cancer Center and State Key Laboratory of Biotherapy and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 40576414 DOI: 10.1021/acs.jmedchem.5c01141
Abstract

Blockade of the A2A Adenosine Receptor (A2AAR) by small-molecule antagonists holds promise for enhancing the efficacy of immune checkpoint inhibitors such as PD-L1 antibodies. However, many A2AAR antagonists suffer from limited clinical success due to poor metabolic stability. In this study, we introduce chirality into the A2AAR antagonist scaffold to address this challenge. This approach led to the discovery of (S)-E8, a chiral compound with markedly improved binding affinity, cellular activity, and in vivo potency compared with AZD4635, a Phase II clinical candidate. In contrast, its enantiomer (R)-E8 displays rapid metabolism and low efficacy, highlighting the importance of stereochemistry for therapeutic performance. Mechanistic studies identified CYP1A2 as the primary enzyme driving the metabolic differences among the enantiomers. These findings underscore the value of chirality-guided design in optimizing drug-like properties and reveal CYP1A2's pivotal role in enantioselective metabolism, offering a promising direction for the development of next-generation A2AAR antagonists.

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