Abstract
Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Aza Compounds / chemical synthesis
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Aza Compounds / chemistry
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Aza Compounds / pharmacology*
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / metabolism
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Dose-Response Relationship, Drug
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacology*
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Molecular Structure
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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 / metabolism
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Rats
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Structure-Activity Relationship
Substances
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5-azaindole
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Aza Compounds
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Cell Cycle Proteins
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Indoles
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Protein Kinase Inhibitors
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CDC7 protein, human
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Protein Serine-Threonine Kinases