Abstract
The epidermal growth factor receptor (EGFR) is a therapeutic target (oncotarget) in NSCLC. Using in vitro EGFR kinase activity system, we identified a novel small molecule, WB-308, as an inhibitor of EGFR. WB-308 decreased NSCLC cell proliferation and colony formation, by causing G2/M arrest and apoptosis. Furthermore, WB-308 inhibited the engraft tumor growths in two animal models in vivo (lung orthotopic transplantation model and patient-derived engraft mouse model). WB-308 impaired the phosphorylation of EGFR, AKT, and ERK1/2 protein. WB-308 was less cytotoxic than Gefitinib. Our study suggests that WB-308 is a novel EGFR-TKI and may be considered to substitute for Gefitinib in clinical therapy for NSCLC.
Keywords:
EGFR; NSCLC; TKIs; tumor growth.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / toxicity
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Apoptosis / drug effects
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Carbolines / chemistry
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Carbolines / pharmacology*
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Carbolines / toxicity
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / enzymology
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Dose-Response Relationship, Drug
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / chemistry
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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G2 Phase Cell Cycle Checkpoints / drug effects
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Gefitinib
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / enzymology
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Mice, Nude
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Molecular Docking Simulation
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Molecular Targeted Therapy
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Mutation
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Phosphorylation
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Protein Conformation
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / toxicity
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Proto-Oncogene Proteins c-akt / metabolism
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Quinazolines / pharmacology
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Signal Transduction / drug effects
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Time Factors
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Transfection
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Carbolines
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Protein Kinase Inhibitors
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Quinazolines
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WB-38 compound
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EGFR protein, human
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Gefitinib