Abstract
A series of substituted imidazo[1,2-a]pyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Aurora Kinases
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Breast Neoplasms / drug therapy
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Breast Neoplasms / enzymology*
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Breast Neoplasms / genetics
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Computer Simulation
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DNA-Binding Proteins / metabolism
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Dasatinib
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Dose-Response Relationship, Drug
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Drug Design
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Drug Discovery
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Drug Screening Assays, Antitumor
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Female
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology*
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Inhibitory Concentration 50
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Melanocytes / physiology
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Mice
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Molecular Targeted Therapy
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Oncogenes
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Phenotype
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Proto-Oncogenes
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Pyrazines / chemical synthesis*
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Pyrazines / chemistry
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Pyrazines / pharmacokinetics
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Pyrazines / pharmacology*
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Pyrimidines / metabolism
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RNA-Binding Proteins / metabolism
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Structure-Activity Relationship
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Thiazoles / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Imidazoles
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KHDRBS1 protein, human
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Pyrazines
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Pyrimidines
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RNA-Binding Proteins
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Thiazoles
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Protein-Tyrosine Kinases
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PTK6 protein, human
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Aurora Kinases
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Protein Serine-Threonine Kinases
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Dasatinib