title: An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases.
abstract: BACKGROUND
  The oncogenic RET/PTC tyrosine kinase causes papillary thyroid cancer (PTC). The use of inhibitors specific for RET/PTC may be useful for targeted therapy of PTC.
  
  
  OBJECTIVE
  The objective of the study was to evaluate the efficacies of the recently developed kinase inhibitors SU11248, SU5416, and SU6668 in inhibition of RET/PTC.
  
  
  METHODS
  SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay. The inhibitory effects of the compounds on RET/PTC were evaluated by quantifying the autophosphorylation of RET/PTC, signal transducer and activator of transcription (STAT)-3 activation, and the morphological reversal of RET/PTC-transformed cells.
  
  
  RESULTS
  An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC(50) of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248. Thus, SU11248 effectively inhibits the kinase activity of RET/PTC3. RET/PTC-mediated Y705 phosphorylation of STAT3 was inhibited by addition of SU11248, and the inhibitory effects of SU11248 on the tyrosine phosphorylation and transcriptional activation of STAT3 were very closely correlated with decreased autophosphorylation of RET/PTC. SU11248 caused a complete morphological reversion of transformed NIH-RET/PTC3 cells and inhibited the growth of TPC-1 cells that have an endogenous RET/PTC1.
  
  
  CONCLUSIONS
  SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.
authors.affiliation: Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University School of Medicine, 640 Daesadong Chungku, Daejon 301-721, Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Jung
authors.forename: Hyo Kyun
authors.initials: HK
authors.lastname: Chung
authors.forename: Jung Hun
authors.initials: JH
authors.lastname: Song
authors.forename: Ki Cheol
authors.initials: KC
authors.lastname: Park
authors.forename: Su Hyeon
authors.initials: SH
authors.lastname: Park
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: So Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ki-Won
authors.initials: KW
authors.lastname: Jo
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D000078183:Oxindoles; D010766:Phosphorylation; D011422:Propionates; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C116890:Semaxinib; C412603:orantinib; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D000077210:Sunitinib