Small molecule c-MET inhibitor PHA665752: effect on cell growth and motility in papillary thyroid carcinoma

Head Neck. 2008 Aug;30(8):991-1000. doi: 10.1002/hed.20816.


Background: c-Met is upregulated in papillary thyroid carcinoma (PTC) and can be an attractive therapeutic target. We tested the effects of the small molecule c-met inhibitor PHA665752 in blocking c-met-dependent phenotypic effects in PTC cell lines.

Methods: PTC patient tissues and cell lines were evaluated for c-met expression. The effect of PHA665752 on c-met phosphorylation, downstream signaling, hepatocyte growth factor (HGF)-dependent cell growth, and induction of apoptosis was studied. The IC(50) of PHA665752 in c-met-expressing PTC cells was determined, and growth curves at 0.1x, 1x, and 10x IC(50) concentrations were obtained. Poly(ADP-ribose) polymerase (PARP) and caspase-9-processing post-PHA665752 treatment were studied as markers of apoptosis, and assays analyzing HGF-dependent cell invasion and migration in the presence and absence of PHA665752 were done.

Results: c-Met was upregulated in most of the patient tissues with PTC and in many PTC cell lines. PHA665752 specifically inhibited c-met phosphorylation, c-met-dependent cell growth, signal transduction, cell survival, cell invasion, and migration in PTC cells with high c-met.

Conclusions: PHA665752 is an effective and specific inhibitor of c-met in PTC cells with high levels of c-met expression.

Publication types

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

MeSH terms

  • Apoptosis / drug effects
  • Carcinoma, Papillary / drug therapy*
  • Carcinoma, Papillary / metabolism
  • Carcinoma, Papillary / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Indoles / pharmacology*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Sulfones / pharmacology*
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology


  • 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
  • Indoles
  • Sulfones
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases