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Submitted on December 30, 2005
Accepted on July 7, 2006
Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 301-721, Korea. Department of Biochemistry, Seonam University College of Medicine, Namwon 590-711 Korea. Laboratory of Radiation Experimental Therapeutics, Korea Institute of Radiological & Medical Sciences, Seoul, 139-706 Korea. Protein Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeundong, Yusonku Daejeon, 305-333, Korea
* To whom correspondence should be addressed. E-mail: minhos{at}cnu.ac.kr.
Context: 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: To evaluate the efficacies of the recently developed kinase inhibitors SU11248, SU5416, and SU6668 in inhibition of RET/PTC.
Design: 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, STAT3 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 a 50% inhibitory concentration (IC50) 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 which have an endogenous RET/PTC1.
Conclusion: SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.
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