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

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 IC50 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.