Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin

Mol Cancer Ther. 2011 Aug;10(8):1394-406. doi: 10.1158/1535-7163.MCT-10-1099. Epub 2011 Jun 14.


The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC(50) values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Kα, PI3Kβ, PI3Kγ, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling. OSI-027 shows concentration-dependent pharmacodynamic effects on phosphorylation of 4E-BP1 and AKT in tumor tissue with resulting tumor growth inhibition. OSI-027 shows robust antitumor activity in several different human xenograft models representing various histologies. Furthermore, in COLO 205 and GEO colon cancer xenograft models, OSI-027 shows superior efficacy compared with rapamycin. Our results further support the important role of mTOR as a driver of tumor growth and establish OSI-027 as a potent anticancer agent. OSI-027 is currently in phase I clinical trials in cancer patients.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Activation / drug effects
  • Female
  • HeLa Cells
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Multiprotein Complexes
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors*
  • Triazines / chemistry
  • Triazines / pharmacokinetics
  • Triazines / pharmacology*
  • Xenograft Model Antitumor Assays


  • CRTC2 protein, human
  • Imidazoles
  • Multiprotein Complexes
  • OSI 027
  • Protein Kinase Inhibitors
  • Proteins
  • Transcription Factors
  • Triazines
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • Sirolimus