7DY7

Discovery of Novel Small-molecule Inhibitors of PD-1/PD-L1 Axis that Promotes PD-L1 Internalization and Degradation

Summary for 7DY7

• Entry DOI: 10.2210/pdb7dy7/pdb
• Descriptor: Programmed cell death 1 ligand 1, 2-[[3-[[5-(2-methyl-3-phenyl-phenyl)-1,3,4-oxadiazol-2-yl]amino]phenyl]methylamino]ethanol (3 entities in total)
• Functional Keywords: immune checkpoint, inhibitor, complex, dimer, immunosuppressant
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 29205.40

Authors

Cheng, Y.,Wang, T.Y.,Lu, M.L.,Jiang, S.,Xiao, Y.B. (deposition date: 2021-01-20, release date: 2022-01-26, Last modification date: 2024-10-16)

Primary citation

Wang, T.,Cai, S.,Cheng, Y.,Zhang, W.,Wang, M.,Sun, H.,Guo, B.,Li, Z.,Xiao, Y.,Jiang, S.
Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation.
J.Med.Chem., 65:3879-3893, 2022

PubMed Abstract: Several monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway have been used successfully in anticancer immunotherapy. Inherent limitations of antibody-based therapies remain, however, and alternative small-molecule inhibitors that can block the PD-1/PD-L1 axis are urgent needed. Herein, we report the discovery of compound as a bifunctional inhibitor of PD-1/PD-L1 interactions. inhibits PD-1/PD-L1 interactions and promotes dimerization, internalization, and degradation of PD-L1. promotes cell-surface PD-L1 internalized into the cytosol and induces the degradation of PD-L1 in tumor cells through a lysosome-dependent pathway. Furthermore, suppresses tumor growth by activating antitumor immunity. These results demonstrate that targets the PD-1/PD-L1 axis and induces PD-L1 degradation.

PubMed: 35188766
DOI: 10.1021/acs.jmedchem.1c01682

Experimental method

X-RAY DIFFRACTION (2.42 Å)