Abstract
Reactivation of the wild-type p53 pathway is one key goal aimed at developing targeted therapeutics in the cancer research field. Although most p53 protein kinases form 'p53-activating' signals, there are few kinases whose action can contribute to the inhibition of p53, as Casein kinase 1 (CK1) and Checkpoint kinase 1 (CHK1). Here we report on a pyrazolo-pyridine analogue showing activity against both CK1 and CHK1 kinases that lead to p53 pathway stabilisation, thus having pharmacological similarities to the p53-activator Nutlin-3. These data demonstrate the emerging potential utility of multivalent kinase inhibitors.
Keywords:
Casein kinase 1; Checkpoint kinase 1; Kinase inhibitor; p53 Pathway activation.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Casein Kinase I / antagonists & inhibitors*
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Casein Kinase I / genetics
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Casein Kinase I / metabolism
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Cell Cycle Checkpoints / drug effects
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Cell Line
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Cell Survival / drug effects
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Checkpoint Kinase 1
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HCT116 Cells
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Humans
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Kinetics
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / toxicity
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Protein Kinases / chemistry*
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Protein Kinases / metabolism
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / toxicity
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / toxicity
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RNA Interference
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RNA, Small Interfering / pharmacology
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Tumor Suppressor Protein p53 / agonists*
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Tumor Suppressor Protein p53 / metabolism
Substances
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Protein Kinase Inhibitors
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Pyrazoles
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Pyridines
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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pyrazolopyridine
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Protein Kinases
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CHEK1 protein, human
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Casein Kinase I
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Checkpoint Kinase 1