Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A2 receptors

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外文摘要：The adenosine subfamily G protein-coupled receptors A2AR and A2BR have been identified as promising cancer immunotherapy candidates.One of the A2AR/A2BR dual antagonists,AB928,has progressed to a phase Ⅱ clinical trial to treat rectal cancer.However,the precise mechanism underlying its dual-antagonistic properties remains elusive.Herein,we report crystal structures of the A2AR complexed with AB928 and a selective A2AR antagonist 2-118.The structures revealed a common binding mode on A2AR,wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets.In contrast,the cAMP assay and A2AR and A2BR molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A2BR.Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A2BR pocket,while 2-118 did not due to intrinsic differences.This disparity potentially accounted for the difference in inhibitory efficacy between A2BR and A2AR.This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A2AR/A2BR for cancer therapy.

外文关键词：

adenosine receptorA2ARA2BRinhibitordual-antagonismdrug discovery

作者：

Yuan Weng、Xinyu Yang、Qiansen Zhang、Ying Chen、Yueming Xu、Chenyu Zhu、Qiong Xie、Yonghui Wang、Huaiyu Yang、Mingyao Liu、Weiqiang Lu、Gaojie Song

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作者单位：

Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai 200241,China

Department of Medicinal Chemistry,School of Pharmacy,Fudan University,Shanghai 201203,China

基金：

National Key Research and Development Program of ChinaBasic Research Program of Science and Technology Commission of Shanghai MunicipalityNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key Scientific Infrastructure for Translational Medicine(Shanghai)Instruments Sharing Platform of the School of Life Sciences,East China Normal UniversityECNU Multifunctional Platform for Innovation

项目编号：

2018YFA050700121JC140240032171215.81972828.82172644.8227385781830083TMSK-2021-120001

出版年：

2024

DOI：

10.1007/s11427-023-2459-8

中国科学:生命科学(英文版)

中国科学院

中国科学:生命科学(英文版)

CSTPCD

影响因子：0.806

ISSN：1674-7305

年,卷(期)：2024.67(5)