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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line, Tumor , Drug Design , High-Throughput Screening Assays , Humans , Inhibitory Concentration 50 , Male , Mice , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction , Solubility , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.