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An Orally Administered Multitarget Tyrosine Kinase Inhibitor, SU11248, Is a Novel Potent Inhibitor of Thyroid Oncogenic RET/Papillary Thyroid Cancer Kinases

Laboratory of Endocrine Cell Biology (D.W.K., Y.S.J., H.S.J., H.K.C., J.H.S., K.C.P., S.H.P., J.H.H., S.Y.R., M.S.), National Research Laboratory Program, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721, Korea; Department of Biochemistry (G.R.K.), Seonam University College of Medicine, Namwon 590-711, Korea; Laboratory of Radiation Experimental Therapeutics (S.-J.L.), Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea; and Protein Therapeutics Research Center (K.-W.J.), Korea Research Institute of Bioscience and Biotechnology, Yusonku Daejeon 305-333, Korea

Address all correspondence and requests for reprints to: Minho Shong, Laboratory of Endocrine Cell Biology, Department of Internal Medicine, Chungnam National University School of Medicine, 640 Daesadong Chungku Daejon 301-721 Korea. 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: 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.

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, 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 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 that have an endogenous RET/PTC1.

Conclusion: SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.

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