8JBA

Discovery and Crystallography Study of Novel Oxadiazole Analogs as Small Molecule PD-1/PD-L1 inhibitors

Summary for 8JBA

• Entry DOI: 10.2210/pdb8jba/pdb
• Descriptor: Programmed cell death 1 ligand 1, (2~{S})-2-[[3-[[5-[(2-methyl-3-phenyl-phenoxy)methyl]-1,3,4-oxadiazol-2-yl]sulfanylmethyl]phenyl]methylamino]-3-oxidanyl-propanoic acid (3 entities in total)
• Functional Keywords: immune checkpoint, dimer, inhibitor, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 29863.10

Authors

Cheng, Y.,Xiao, Y.B. (deposition date: 2023-05-08, release date: 2023-10-25, Last modification date: 2024-10-23)

Primary citation

Liu, J.,Cheng, Y.,Yuan, L.,Liu, T.,Ruan, Y.,Ren, Y.,Li, L.,Jiang, S.,Xiao, Y.,Chen, J.
Discovery and Crystallography Study of Novel Biphenyl Ether and Oxadiazole Thioether (Non-Arylmethylamine)-Based Small-Molecule PD-1/PD-L1 Inhibitors as Immunotherapeutic Agents.
J.Med.Chem., 66:13172-13188, 2023

PubMed Abstract: Current small-molecule PD-1/PD-L1 inhibitors are mainly based on the arylmethylamine/biphenyl core scaffold. Herein, we designed for the first time a series of non-arylmethylamine analogues (oxadiazole thioether derivatives) as small-molecule PD-1/PD-L1 inhibitors. Among them, compound exhibited the most potent PD-L1 inhibitory activity with an IC of 16.7 nM, 3.2-fold better than the lead (IC = 53.6 nM). The X-ray crystal structure of in complex with PD-L1 was solved at a resolution of 2.6 Å, which further confirmed the high binding affinity of to PD-L1. In the HepG2/Jurkat T cell co-culture model, effectively promoted HepG2 cell death by restoring the immune function of T cells. In addition, showed excellent antitumor efficacy (TGI = 88.6% at 30 mg/kg) and benign toxicity profiles in a B16-F10 tumor model by modulating PD-L1. In summary, represents the first non-arylmethylamine-based small-molecule PD-1/PD-L1 inhibitor worthy of further investigation.

PubMed: 37674362
DOI: 10.1021/acs.jmedchem.3c01141

Experimental method

X-RAY DIFFRACTION (2.6 Å)