Abstract
As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Proliferation / drug effects
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Clinical Trials, Phase I as Topic
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Inhibitory Concentration 50
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Mice
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Mice, Nude
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Molecular Structure
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Neoplasms / drug therapy
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Polo-Like Kinase 1
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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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Proto-Oncogene Proteins / antagonists & inhibitors*
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Quinazolines / chemical synthesis
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Quinazolines / chemistry
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Quinazolines / pharmacology*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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NMS P937
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrazoles
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Quinazolines
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Protein Serine-Threonine Kinases