Abstract
The discovery of 1-(5-chloro-2-alkoxyphenyl)-3-(5-cyanopyrazin-2-yl)ureas as a new class of potent (IC(50) values of 3-10 nM) and selective inhibitors of Chk1 kinase was described. One of these compounds (2e) potentiates HeLa cells by over 22-fold against doxorubicin in an antiproliferation assay, and SW620 cells against camptothecin by 20-fold in an antiproliferation assay and 14-fold in a soft agar assay. Flow cytometry (FACS) analysis confirmed that 2e abrogated G2 checkpoint arrest of H1299 cells caused by doxorubicin and S checkpoint arrest caused by camptothecin.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Camptothecin / pharmacology
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Cell Cycle / drug effects
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Checkpoint Kinase 1
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Crystallography, X-Ray
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Doxorubicin / pharmacology
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Drug Screening Assays, Antitumor
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HeLa Cells
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Humans
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Nitriles / chemical synthesis*
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Nitriles / pharmacology
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinases / metabolism*
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacology
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Structure-Activity Relationship
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / pharmacology
Substances
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Antineoplastic Agents
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Nitriles
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Protein Kinase Inhibitors
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Pyrazoles
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Doxorubicin
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Urea
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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Camptothecin