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Pyrazolopyrimidines as dual Akt/p70S6K inhibitors

Kenneth D Rice1, Moon H Kim, Joerg Bussenius

  • 1Exelixis, 210 E. Grand Avenue, South San Francisco, CA 94080, USA.

Bioorganic & Medicinal Chemistry Letters
|March 28, 2012
PubMed

Insights

Targeting the PI3K pathway in cancer is crucial. Dual inhibitors targeting Akt and p70S6K offer a promising strategy for effective tumor growth inhibition, with lead compound 11b advancing to clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a critical regulator of cell growth and survival, frequently dysregulated in human cancers.
  • Selective inhibition of p70S6Kinase, a downstream effector in this pathway, has shown limited efficacy due to compensatory activation of upstream kinases like Akt via feedback loops.
  • This suggests that targeting multiple nodes within the PI3K pathway may be necessary for potent anti-cancer activity.

Purpose of the Study:

  • To design novel dual inhibitors targeting both Akt and p70S6K kinases within the PI3K/Akt/mTOR pathway.
  • To evaluate the in vivo efficacy of a lead dual inhibitor compound.

Main Methods:

  • Chemical synthesis and design of dual Akt/p70S6K inhibitors.
  • In vitro kinase assays to confirm inhibitory activity.
  • In vivo studies to assess the anti-tumor efficacy of the lead compound.

Main Results:

  • Successful design and synthesis of potent dual Akt/p70S6K inhibitors.
  • Identification of compound 11b as a lead candidate with significant in vivo anti-tumor activity.
  • Compound 11b demonstrated efficacy in preclinical models, warranting further clinical investigation.

Conclusions:

  • Dual inhibition of Akt and p70S6K represents a viable therapeutic strategy for cancers driven by the PI3K/Akt/mTOR pathway.
  • The lead compound 11b shows promise as a novel anti-cancer agent and has been advanced into clinical development.

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