Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A_(2)receptors  

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 

机构地区：[1]Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai 200241,China [2]Department of Medicinal Chemistry,School of Pharmacy,Fudan University,Shanghai 201203,China

出　　处：《Science China(Life Sciences)》2024年第5期986-995,共10页中国科学（生命科学英文版）

基　　金：supported by the National Key Research and Development Program of China(2018YFA0507001);the Basic Research Program of Science and Technology Commission of Shanghai Municipality(21JC1402400);the National Natural Science Foundation of China(32171215,81972828,82172644,82273857 and 81830083);the National Key Scientific Infrastructure for Translational Medicine(Shanghai)(TMSK-2021-120)。

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

关 键 词：adenosine receptor A2AR A2BR INHIBITOR dual-antagonism drug discovery 

分 类 号：R730.51[医药卫生—肿瘤]