Dual inhibitors of PI3K/mTOR or mTOR-selective inhibitors: which way shall we go?

Curr Med Chem. 2011;18(36):5528-44. doi: 10.2174/092986711798347298.

Abstract

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway is a central regulator in cell proliferation, growth, and angiogenesis. Inhibition of this pathway therefore is a major strategy for cancer chemotherapy. In order to induce the maximal therapeutic outcome in cancer treatment, vertical inhibition of the PI3K/AKT/mTOR pathway or horizontal inhibition of PI3K/AKT/mTOR and other kinases has been reported. In this review, we discuss the drug design and clinical development of dual inhibitors of PI3K and mTOR as well as the mTOR-selective inhibitors, classified based on the mechanism of action and the chemical structures. Structural determinants for increasing selectivity toward PI3Kα or mTOR are revealed from the structure-activity relationship of the reported inhibitors. Current clinical development in combination therapy of inhibitors involving in the PI3K/AKT/mTOR pathway is also discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Targeted Therapy / methods
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Substrate Specificity
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases