Abstract
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Computer Simulation
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Humans
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Mice
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Neoplasms / drug therapy
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary
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Pyrimidinones / chemistry*
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Pyrimidinones / pharmacokinetics*
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Pyrimidinones / therapeutic use
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Rats
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Structure-Activity Relationship
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Transplantation, Heterologous
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Up-Regulation
Substances
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Cell Cycle Proteins
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Protein Kinase Inhibitors
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Pyrimidinones
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XL413 compound
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CDC7 protein, human
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Protein Serine-Threonine Kinases