Abstract
A novel series of N(4)-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine kinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer.
MeSH terms
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Acrylamides / chemical synthesis*
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Acrylamides / pharmacokinetics
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Acrylamides / pharmacology
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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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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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ErbB Receptors / antagonists & inhibitors*
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Female
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Humans
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Lapatinib
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Mice
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Mice, Inbred ICR
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Models, Molecular
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Mutation
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Oxazoles / chemical synthesis*
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Oxazoles / pharmacokinetics
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Oxazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Quinazolines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, ErbB-2 / antagonists & inhibitors*
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Stomach Neoplasms / drug therapy
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Stomach Neoplasms / genetics
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Structure-Activity Relationship
Substances
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Acrylamides
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Antineoplastic Agents
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N-((2-(4-amino-6-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)pyrimidin-5-yl)oxazol-4-yl)methyl)acrylamide
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Oxazoles
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Pyrimidines
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Quinazolines
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Lapatinib
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EGFR protein, human
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ERBB2 protein, human
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ErbB Receptors
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Receptor, ErbB-2