Dissecting the role of mTOR: lessons from mTOR inhibitors

Biochim Biophys Acta. 2010 Mar;1804(3):433-9. doi: 10.1016/j.bbapap.2009.12.001. Epub 2009 Dec 11.

Abstract

Recent years have observed significant advances in our understanding of how the serine/threonine kinase target of rapamycin (TOR) controls key cellular processes such as cell survival, growth and proliferation. Consistent with its role in cell proliferation, the mTOR pathway is frequently hyperactivated in a number of human malignancies and is thus considered to be an attractive target for anti-cancer therapy. Rapamycin and its analogs (rapalogs) function as allosteric inhibitors of mTORC1 and are currently used in the treatment of advanced renal cell carcinoma. Rapamycin and its derivatives bind to the small immunophilin FKBP12 to inhibit mTORC1 signalling through a poorly understood mechanism. Rapamycin/FKBP12 efficiently inhibit some, but not all, functions of mTOR and hence much interest has been placed in the development of drugs that target the kinase activity of mTOR directly. Several novel active-site inhibitors of mTOR, which inhibit both mTORC1 and mTORC2, were developed in the last year. In this manuscript, we provide a brief outline of our current understanding of the mTOR signalling pathway and review the molecular underpinnings of the action of rapamycin and novel active-site mTOR inhibitors as well as potential advantages and caveats associated with the use of these drugs in the treatment of cancer.

Publication types

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

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / enzymology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteins
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases
  • Tacrolimus Binding Protein 1A / antagonists & inhibitors
  • Tacrolimus Binding Protein 1A / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism

Substances

  • CRTC2 protein, human
  • Immunosuppressive Agents
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Proteins
  • Transcription Factors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Tacrolimus Binding Protein 1A
  • Sirolimus