Abstract
A piperazine series of cyclin-dependent kinase (CDK) inhibitors have been identified. The compounds exhibit excellent physiochemical properties and a novel binding mode, whereby a bridging interaction via a water molecule with Asp 86 of CDK2, leads to selectivity for the CDK family of enzymes over other kinases. Piperazines 2e and 2i were subsequently shown to inhibit tumour growth when dosed orally in a nude mouse xenograft study. Additional chemical series that exploit this unexpected interaction with Asp 86 are also described.
MeSH terms
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Animals
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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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Aspartic Acid / chemistry
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Aspartic Acid / genetics
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Binding Sites
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Combinatorial Chemistry Techniques
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Drug Design
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Mice
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Mice, Nude
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Molecular Structure
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Imidazoles
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Piperazines
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Aspartic Acid
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases