Abstract
Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Amides / chemistry
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Binding Sites
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Checkpoint Kinase 1
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Crystallography, X-Ray
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Drug Design
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Ethylenediamines / chemistry
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Humans
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Hydrogen Bonding
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Kinetics
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Molecular Dynamics Simulation
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Molecular Structure
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis*
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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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Pyridines / chemical synthesis*
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Pyridines / pharmacology
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / pharmacology
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Water / chemistry
Substances
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Amides
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Antineoplastic Agents
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Ethylenediamines
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Protein Kinase Inhibitors
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Pyridines
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Thiazoles
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Water
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Protein Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1