Abstract
Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Cell Line
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Checkpoint Kinase 2
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Crystallography, X-Ray
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Drug Design
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / metabolism
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HT29 Cells
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Humans
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In Vitro Techniques
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Mice
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Models, Molecular
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Phenols / chemical synthesis*
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Phenols / chemistry
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Phenols / pharmacology
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Protein Binding
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Quinazolines / chemical synthesis*
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Quinazolines / chemistry
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Quinazolines / pharmacology
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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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Stereoisomerism
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Structure-Activity Relationship
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Thymus Gland / cytology
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Thymus Gland / drug effects
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Thymus Gland / radiation effects
Substances
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4-fluoro-2-(4-(4-(2-hydroxypropan-2-yl)pyrrolidin-3-ylamino)-6,7-dimethoxyquinazolin-2-yl)phenol
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Phenols
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Quinazolines
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Radiation-Protective Agents
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Checkpoint Kinase 2
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CHEK2 protein, human
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases