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Publication Abstract from PubMed

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, B9 was found to inhibit the PD-1/PD-L1 interaction with the best IC(50) value of 1.8 +/- 0.7 nM. Beyond the blockade of the PD-1/PD-L1 axis, B9 promotes the dimerization, internalization, and degradation of PD-L1. Furthermore, B9 displayed high in vivo 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 B9 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.

Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy.,Wang K, Zhang X, Cheng Y, Qi Z, Ye K, Zhang K, Jiang S, Liu Y, Xiao Y, Wang T J Med Chem. 2023 Dec 28;66(24):16807-16827. doi: 10.1021/acs.jmedchem.3c01534. , Epub 2023 Dec 18. PMID:38109261^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.