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.

基于程序性死亡蛋白配体1（programmed death protein ligand 1, PD-L1）与表皮生长因子受体（epidermal growth factor receptor, EGFR）在胶质母细胞瘤（glioblastoma, GBM）中的密切关联，我们设计并合成了一系列可同时靶向EGFR与PD-L1的小分子双重抑制剂。其中，化合物EP26对EGFR的半数抑制浓度（IC50）为37.5 nM，对PD-1/PD-L1相互作用的半数抑制浓度为1.77 μM，展现出最优的抑制活性。此外，在U87MG/Jurkat细胞共培养模型中，EP26可促进U87MG细胞死亡，展现出更优异的体外抗增殖活性与免疫调节效应。进一步研究表明，EP26具备良好的药代动力学特性（生物利用度F=22%），在胶质母细胞瘤小鼠模型中，其肿瘤生长抑制率（tumor growth inhibition, TGI）达92.0%，疗效优于吉非替尼（Gefitinib，TGI=77.2%）与NP19（TGI=82.8%）。此外，EP26可上调肿瘤微环境中的CD4+细胞与CD8+细胞水平。综上，上述结果表明EP26是首个基于小分子的PD-L1/EGFR双重抑制剂，有望作为癌症治疗的免疫调节剂开展后续研究。