Scientific article

Inhibition of RET tyrosine kinase by SU5416

Published inJournal of Molecular Endocrinology, vol. 37, no. 2, p. 199-212
Publication date2006-10

Thyroid neoplasia is frequently associated with rearranged during transfection (RET) proto-oncogene mutations that cause hyperactivation of RET kinase activity. Selective inhibition of RET-mediated signaling should lead to an efficacious therapy. SU5416 is a potent inhibitor of vascular endothelial cell growth factor receptor, c-Kit, and FLT-3 receptor tyrosine kinases presently used in clinical trials. We found that SU5416 inhibits RET with similar potency, both in cell-free assays and in cells, thus causing proliferation arrest in oncogenic RET-transfected cells and in papillary thyroid carcinoma (PTC) cells expressing the RET/PTC1 oncogene, but not in RET-negative control cells. SU5416 inhibited RET-mediated signaling through the extracellular signal regulated kinase (ERK) and JNK pathways. In addition, we show that a naturally occurring MEN2 mutation at codon 804 confers resistance to SU5416, but not to the related compound SU4984. We provide a possible explanation to these results by using molecular docking. Finally, SU5416 was also assessed against an array of 52 tyrosine and serine/threonine kinases.

Citation (ISO format)
MOLOGNI, Luca et al. Inhibition of RET tyrosine kinase by SU5416. In: Journal of Molecular Endocrinology, 2006, vol. 37, n° 2, p. 199–212. doi: 10.1677/jme.1.01999
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Article (Published version)
ISSN of the journal0952-5041

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