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Publication Abstract from PubMed

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 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 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.

Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A(2) receptors.,Weng Y, Yang X, Zhang Q, Chen Y, Xu Y, Zhu C, Xie Q, Wang Y, Yang H, Liu M, Lu W, Song G Sci China Life Sci. 2024 May;67(5):986-995. doi: 10.1007/s11427-023-2459-8. Epub , 2024 Jan 31. PMID:38319473^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.