The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations

Clin Cancer Res. 2011 May 15;17(10):3272-81. doi: 10.1158/1078-0432.CCR-10-2882. Epub 2011 May 10.


Purpose: The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. PIK3CA mutations, which are found in many cancer patients, activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel PI3K inhibitor. Thus, this study aimed to clarify the biochemical and antitumor activity of CH5132799 and elucidate the correlation between CH5132799 response and genetic alterations in the PI3K pathway.

Experimental design: Kinase inhibitory activity was profiled in cell-free assays. A large panel of human breast, ovarian, prostate, and endometrial cancer cell lines, as well as xenograft models, were used to evaluate the antitumor activity of CH5132799, followed by analysis for genetic alterations. Effects on Akt phosphorylation induced by mTORC1 inhibition were tested with CH5132799 and compared with mTORC1 and PI3K/mTOR inhibitors.

Results: CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment.

Conclusions: CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy
  • Mutation / physiology
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Oncogenes / genetics
  • Oncogenes / physiology
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyrimidines / therapeutic use*
  • Substrate Specificity
  • Sulfonamides / therapeutic use*
  • Xenograft Model Antitumor Assays


  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines
  • Sulfonamides
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • CH 5132799