8K5N

Discovery of Novel PD-L1 Inhibitors That Induce Dimerization and Degradation of PD-L1 Based on Fragment Coupling Strategy

Summary for 8K5N

• Entry DOI: 10.2210/pdb8k5n/pdb
• Descriptor: Programmed cell death 1 ligand 1, 3-[(1~{S})-1-[6-methoxy-3-methyl-5-[[[(2~{S})-5-oxidanylidenepyrrolidin-2-yl]methylamino]methyl]pyridin-2-yl]oxy-2,3-dihydro-1~{H}-inden-4-yl]-2-methyl-~{N}-[5-[[[(2~{S})-5-oxidanylidenepyrrolidin-2-yl]methylamino]methyl]pyridin-2-yl]benzamide (3 entities in total)
• Functional Keywords: immune checkpoint, dimer, small molecule inhibitor, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 30075.37

Authors

Cheng, Y.,Xiao, Y.B. (deposition date: 2023-07-22, release date: 2024-01-03, Last modification date: 2024-10-09)

Primary citation

Wang, K.,Zhang, X.,Cheng, Y.,Qi, Z.,Ye, K.,Zhang, K.,Jiang, S.,Liu, Y.,Xiao, Y.,Wang, T.
Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy.
J.Med.Chem., 66:16807-16827, 2023

PubMed Abstract: Tumor cells can evade immune surveillance through overexpressing programmed cell death-ligand 1 (PD-L1) to interact with programmed cell death-1 (PD-1). Besides, tumor-intrinsic PD-L1 is involved in tumor progression without interaction with PD-1, which provides more challenges for the discovery of PD-L1 inhibitors. Herein, we report the discovery of novel PD-L1 inhibitors using the fragment coupling strategy. Among them, was found to inhibit the PD-1/PD-L1 interaction with the best IC value of 1.8 ± 0.7 nM. Beyond the blockade of the PD-1/PD-L1 axis, promotes the dimerization, internalization, and degradation of PD-L1. Furthermore, displayed high antitumor efficacy in the CT26 mouse model and activated the immune microenvironment and induced PD-L1 degradation of PD-L1 in the tumor. These results show that is a promising lead PD-L1 inhibitor through the blockade of PD-1/PD-L1 interaction and functional inhibition of the PD-L1 signal pathway.

PubMed: 38109261
DOI: 10.1021/acs.jmedchem.3c01534

Experimental method

X-RAY DIFFRACTION (2.2 Å)