Abstract
The discovery of a series of novel, potent, and highly selective inhibitors of the DNA damage control kinase chk2 is disclosed. Here we report the first SAR study around inhibitors of this kinase. High-throughput screening of purified human chk2 led to the identification of a novel series of 2-arylbenzimidazole inhibitors of the kinase. Optimization was facilitated using homology models of chk2 and docking of inhibitors, leading to the highly potent 2-arylbenzimidazole 2h (IC(50) 15 nM). Compound 2h is an ATP-competitive inhibitor of chk2 that dose dependently protects human CD4(+) and CD8(+) T-cells from apoptosis due to ionizing radiation. This work suggests that a selective small molecule inhibitor of chk2 could be a useful adjuvant to radiotherapy, increasing the therapeutic window of such treatment.
MeSH terms
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Adenosine Triphosphate / chemistry
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Apoptosis / drug effects
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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Binding Sites
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / radiation effects
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / radiation effects
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Checkpoint Kinase 2
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DNA Damage
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Gamma Rays
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Humans
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In Vitro Techniques
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Models, Molecular
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Phenyl Ethers / chemical synthesis*
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Phenyl Ethers / chemistry
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Phenyl Ethers / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Radiation-Protective Agents / chemical synthesis*
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Radiation-Protective Agents / chemistry
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Radiation-Protective Agents / pharmacology
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Structure-Activity Relationship
Substances
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2-(4-(4-chlorophenoxy)phenyl)-1H-benzimidazole-5-carboxylic acid amide
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Benzimidazoles
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Phenyl Ethers
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Radiation-Protective Agents
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Adenosine Triphosphate
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Checkpoint Kinase 2
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CHEK2 protein, human
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Protein Serine-Threonine Kinases