Abstract
From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.
MeSH terms
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Apoptosis / drug effects
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Binding Sites
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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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Drug Evaluation, Preclinical
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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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Humans
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Structure
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Photochemistry
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Protein Kinases / chemistry
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Protein Kinases / drug effects*
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Quinolones / chemical synthesis*
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Quinolones / chemistry
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Quinolones / pharmacology*
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Quinolones
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1