Abstract
The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.
MeSH terms
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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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Biphenyl Compounds / chemical synthesis*
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology
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Breast Neoplasms
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Cell Line, Tumor
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Checkpoint Kinase 1
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Crystallography, X-Ray
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Drug Design
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Drug Screening Assays, Antitumor
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Drug Synergism
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Female
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Gemcitabine
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Humans
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Indazoles / chemistry
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Male
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Models, Molecular
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Molecular Structure
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Prostatic Neoplasms
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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 / chemistry
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Protein Kinases / metabolism*
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Biphenyl Compounds
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Indazoles
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Protein Kinase Inhibitors
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Pyrazoles
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Deoxycytidine
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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Gemcitabine