Abstract
Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment-based drug design and optimized for CHK1 potency and high selectivity using a cell-based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Aminopyridines / chemical synthesis
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Aminopyridines / pharmacology*
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Checkpoint Kinase 1
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Child
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / enzymology
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DNA Damage / drug effects
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Drug Design
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Humans
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Mice
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Mice, Nude
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Mice, Transgenic
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N-Myc Proto-Oncogene Protein
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Neuroblastoma / drug therapy*
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Neuroblastoma / enzymology
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Nuclear Proteins / genetics
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Oncogene Proteins / genetics
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinases / chemistry*
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Protein Kinases / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacology*
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile
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Aminopyridines
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Antineoplastic Agents
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MYCN protein, human
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins
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Oncogene Proteins
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Protein Kinase Inhibitors
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Pyrimidines
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse