Discovery of a series of N-(5-(quinolin-6-yl)pyridin-3-yl)benzenesulfonamides as PI3K/mTOR dual inhibitors

Eur J Med Chem. 2017 Feb 15:127:509-520. doi: 10.1016/j.ejmech.2017.01.016. Epub 2017 Jan 11.

Abstract

Recently, the phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been considered as promising targets for the treatment of cancer. Herein, we synthesized a series of N-(5-(quinolin-6-yl)pyridin-3-yl)benzenesulfonamides as novel PI3K/mTOR dual inhibitors for cancer therapy. In the biological evaluation, compound 17e was identified as a potent PI3K/mTOR dual inhibitor, which significantly inhibit Class I PI3Ks, mTOR and phosphorylation of pAkt(Ser473) at low nanomolar level. Moreover, 17e display high potency against PC-3 cells (IC50 = 80 nM) in the anti-proliferative assay, and showed acceptable pharmacokinetic properties in vivo.

Keywords: Cancer; Inhibitor; PI3K; mTOR.

MeSH terms

  • Animals
  • Benzenesulfonamides
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Humans
  • Male
  • Mice
  • Molecular Docking Simulation
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Conformation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Sulfonamides
  • TOR Serine-Threonine Kinases