Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents
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
Abstract
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