Abstract
A series of isothiazole carboxamidine compounds were synthesized and discovered as novel and selective inhibitors for Chk2. They are not active against the related Chk1 kinase. The structure-activity relationship studies were performed on the scaffold, and enzymatic kinetic analysis showed they are simple ATP competitive inhibitors with K(i) values as low as 11 nM for Chk2. Computer modeling studies were employed to comprehend the mechanism of action and SAR of these compounds.
MeSH terms
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Adenosine Triphosphate / chemistry
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Amidines / chemical synthesis
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Amidines / chemistry*
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Binding, Competitive
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Checkpoint Kinase 2
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Humans
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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 Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Structure-Activity Relationship
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Thiazoles / chemical synthesis
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Thiazoles / chemistry*
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Thiazoles / pharmacology
Substances
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Amidines
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Protein Kinase Inhibitors
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Thiazoles
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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