GSK3 alpha and beta are new functionally relevant targets of tivantinib in lung cancer cells

ACS Chem Biol. 2014 Feb 21;9(2):353-8. doi: 10.1021/cb400660a. Epub 2013 Nov 20.


Tivantinib has been described as a potent and highly selective inhibitor of the receptor tyrosine kinase c-MET and is currently in advanced clinical development for several cancers including non-small cell lung cancer (NSCLC). However, recent studies suggest that tivantinib's anticancer properties are unrelated to c-MET inhibition. Consistently, in determining tivantinib's activity profile in a broad panel of NSCLC cell lines, we found that, in contrast to several more potent c-MET inhibitors, tivantinib reduces cell viability across most of these cell lines. Applying an unbiased, mass-spectrometry-based, chemical proteomics approach, we identified glycogen synthase kinase 3 (GSK3) alpha and beta as novel tivantinib targets. Subsequent validation showed that tivantinib displayed higher potency for GSK3α than for GSK3β and that pharmacological inhibition or simultaneous siRNA-mediated loss of GSK3α and GSK3β caused apoptosis. In summary, GSK3α and GSK3β are new kinase targets of tivantinib that play an important role in its cellular mechanism-of-action in NSCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Cell Line, Tumor
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Lung / drug effects
  • Lung / enzymology
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Molecular Targeted Therapy
  • Pyrrolidinones / pharmacology*
  • Quinolines / pharmacology*


  • ARQ 197
  • Pyrrolidinones
  • Quinolines
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha