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.

中文翻译：

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发现具有高成药性的新型小分子潜在 PD-L1/EGFR 双重抑制剂，用于胶质母细胞瘤免疫治疗


基于胶质母细胞瘤（GBM）中程序性死亡蛋白配体1（PD-L1）与表皮生长因子受体（EGFR）之间的密切关系，我们设计并合成了一系列小分子作为EGFR和PD-L1的潜在双重抑制剂。其中，化合物EP26对EGFR（IC ₅₀ = 37.5 nM）和PD-1/PD-L1相互作用（IC ₅₀ = 1.77 μM）表现出最高的抑制活性。此外，EP26 在 U87MG/Jurkat 细胞共培养模型中通过促进 U87MG 细胞死亡而表现出优异的体外抗增殖活性和体外免疫调节作用。此外，EP26 具有良好的药代动力学特性 (F = 22%)，并且在 GBM 小鼠模型中比吉非替尼 (77.2%) 和 NP19 (82.8%) 更有效地抑制肿瘤生长 (TGI = 92.0%)。此外，EP26 增加了肿瘤微环境中的 CD4 ⁺ 细胞和 CD8 ⁺ 细胞。总的来说，这些结果表明 EP26 代表了第一个基于小分子的 PD-L1/EGFR 双抑制剂，值得进一步研究作为癌症治疗的免疫调节剂。