Abstract
Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.
MeSH terms
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Amino Acid Sequence
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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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Binding Sites
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / chemistry
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Furans / chemical synthesis
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Furans / chemistry
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Furans / pharmacology
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Humans
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Models, Molecular
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Molecular Sequence Data
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Protein Binding
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Pyridones / chemical synthesis*
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Pyridones / chemistry
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Pyridones / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Sequence Homology, Amino Acid
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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Furans
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Pyridones
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Pyrroles
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CDC7 protein, human
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Protein Serine-Threonine Kinases