Abstract
4-anilinoquinazoline-containing inhibitors of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients with mutated EGFR, but they are less effective in multiple myeloma (MM), a fatal malignancy derived from plasma cells. The present study designed a series of novel compounds by conjugating a peroxide bridge to the 4-anilinoquinazoline pharmacophore. Further studies showed that these agents such as 4061 and 4065B displayed potent activity to induce MM cell apoptosis by upregulating pro-apoptotic p53 and Bax while downregulating pro-survival Bcl-2. The mechanistic analysis revealed that both 4061 and 4065B inhibited IGF1-R, AKT and mTOR activation in a concentration dependent manner but had no effects on the expression of their total proteins, suggesting the conjugates of endoperoxide and 4-anilinoquinazoline may exert its anti-myeloma activity by targeting the IGF1-R/AKT/mTOR pathway.
Keywords:
cell death; endoperoxide bridge; multiple myeloma; signaling transduction.
MeSH terms
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacology
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Aniline Compounds / therapeutic use
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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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Apoptosis / drug effects*
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Artemisinins / chemistry
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Artemisinins / pharmacology
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Artemisinins / therapeutic use
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Cell Line, Tumor
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Gefitinib / pharmacology
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Humans
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / pathology
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-akt / metabolism
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Quinazolines / chemistry
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Quinazolines / pharmacology
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Quinazolines / therapeutic use
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Receptor, IGF Type 1 / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism
Substances
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Aniline Compounds
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Antineoplastic Agents
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Artemisinins
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IGF1R protein, human
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Protein Kinase Inhibitors
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Quinazolines
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anilinoquinazoline
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MTOR protein, human
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Receptor, IGF Type 1
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Gefitinib