Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy

Based on the close relationship between programmed death
protein
ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR) in glioblastoma
(GBM), we designed and synthesized a series of small molecules as
potential dual inhibitors of EGFR and PD-L1. Among them, compound EP26 exhibited the highest inhibitory activity against EGFR
(IC50 = 37.5 nM) and PD-1/PD-L1 interaction (IC50 = 1.77 μM). In addition, EP26 displayed superior in vitro antiproliferative activities and in vitro immunomodulatory effects by promoting U87MG cell death in a U87MG/Jurkat
cell coculture model. Furthermore, EP26 possessed favorable
pharmacokinetic properties (F = 22%) and inhibited
tumor growth (TGI = 92.0%) in a GBM mouse model more effectively than
Gefitinib (77.2%) and NP19 (82.8%). Moreover, EP26 increased
CD4+ cells and CD8+ cells in tumor microenvironment.
Collectively, these results suggest that EP26 represents
the first small-molecule-based PD-L1/EGFR dual inhibitor deserving
further investigation as an immunomodulating agent for cancer treatment.