An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases.
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.
Kim
Dong Wook
DW
Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University School of Medicine, 640 Daesadong Chungku, Daejon 301-721, Korea.
Jo
Young Suk
YS
Jung
Hye Sook
HS
Chung
Hyo Kyun
HK
Song
Jung Hun
JH
Park
Ki Cheol
KC
Park
Su Hyeon
SH
Hwang
Jung Hwan
JH
Rha
So Young
SY
Kweon
Gi Ryang
GR
Lee
Su-Jae
SJ
Jo
Ki-Won
KW
Shong
Minho
M
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
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