Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402

J Med Chem. 2010 Jan 28;53(2):798-810. doi: 10.1021/jm9014982.


Herein we describe the identification and lead optimization of triazolopyrimidines as a novel class of potent dual PI3K/mTOR inhibitors, resulting in the discovery of 3 (PKI-402). Compound 3 exhibits good physical properties and PK parameters, low nanomolar potency against PI3Kalpha and mTOR, and excellent inhibition of cell proliferation in several human cancer cell lines. Furthermore, in vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells. In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Class Ib Phosphatidylinositol 3-Kinase
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Isoenzymes / antagonists & inhibitors
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology
  • Rats
  • TOR Serine-Threonine Kinases
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines
  • Triazoles
  • MTOR protein, human
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases