Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy.Despite the inherent advantages of small-molecule inhibitors over antibodies,the discovery of small-molecule inhibitors has fallen behind that of antibody drugs.Based on docking studies between small molecule inhibitor and PD-L1 protein,changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein,which was not reported before.A series of novel phthalimide derivatives from structure-based rational design was synthesized.P39 was identified as the best inhibitor with promising activity,which not only inhibited PD-1/PD-L1 interaction(IC50=8.9 nmol/L),but also enhanced killing efficacy of immune cells on cancer cells.Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins,thereby blocking the binding of PD-1/PD-L1.Moreover,P39 exhibited a favorable safety profile with a LD50＞5000 mg/kg and showed sig-nificant in vivo antitumor activity through promoting CD8+T cell activation.All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization,China Pharmaceutical University,Nanjing 210009,China;Department of Medicinal Chemistry,School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China;Department of Pharmacology,School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China;Beijing Institute of Clinical Pharmacy,Beijing Friendship Hospital,Capital Medical University,Beijing 100050,China;Department of Physics,Chemistry and Pharmacy,University of Southern Denmark,Campusvej 55,5230 Odense,Denmark;Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China

[1]Chengliang Sun;Yao Cheng;Xiaojia Liu;Gefei Wang;Wenjian Min;Xiao Wang;Kai Yuan;Yi Hou;Jiaxing Li;Haolin Zhang;Haojie Dong;Liping Wang;Chenguang Lou;Yanze Sun;Xinmiao Yu;Hongbin Deng;Yibei Xiao;Peng Yang-.Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents)[J].药学学报（英文版）,2022(12):4446-4457

phthalimides,phthalimide,P39

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