Abstract
The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.
Copyright © 2012 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 / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Biological Availability
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Cell Line, Tumor
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Drug Design
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High-Throughput Screening Assays
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Humans
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Inhibitory Concentration 50
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Male
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Mice
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors*
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction
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Solubility
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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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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Ribosomal Protein S6 Kinases, 70-kDa