Abstract
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.
MeSH terms
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Animals
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Antineoplastic Agents* / therapeutic use
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B7-H1 Antigen* / antagonists & inhibitors
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B7-H1 Antigen* / metabolism
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Brain Neoplasms / drug therapy
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Discovery
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ErbB Receptors* / antagonists & inhibitors
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ErbB Receptors* / metabolism
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Glioblastoma* / drug therapy
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Glioblastoma* / pathology
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Immune Checkpoint Inhibitors / chemical synthesis
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Immune Checkpoint Inhibitors / chemistry
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Immune Checkpoint Inhibitors / pharmacokinetics
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Immune Checkpoint Inhibitors / pharmacology
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Immune Checkpoint Inhibitors / therapeutic use
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Immunotherapy / methods
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Mice
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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B7-H1 Antigen
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CD274 protein, human
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EGFR protein, human
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ErbB Receptors
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Immune Checkpoint Inhibitors
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Small Molecule Libraries