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.
Mologni, L., Sala, E., Cazzaniga, S., Rostagno, R., Kuoni, T., Puttini, M., et al. (2006). Inhibition of RET tyrosine kinase by SU5416. JOURNAL OF MOLECULAR ENDOCRINOLOGY, 37(2), 199-212 [10.1677/jme.1.01999].
|Citazione:||Mologni, L., Sala, E., Cazzaniga, S., Rostagno, R., Kuoni, T., Puttini, M., et al. (2006). Inhibition of RET tyrosine kinase by SU5416. JOURNAL OF MOLECULAR ENDOCRINOLOGY, 37(2), 199-212 [10.1677/jme.1.01999].|
|Tipo:||Articolo in rivista - Articolo scientifico|
|Carattere della pubblicazione:||Scientifica|
|Titolo:||Inhibition of RET tyrosine kinase by SU5416|
|Autori:||Mologni, L; Sala, E; Cazzaniga, S; Rostagno, R; Kuoni, T; Puttini, M; Bain, J; Cleris, L; Redaelli, S; Riva, B; Formelli, F; Scapozza, L; Gambacorti-Passerini, C|
|Data di pubblicazione:||ott-2006|
|Rivista:||JOURNAL OF MOLECULAR ENDOCRINOLOGY|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1677/jme.1.01999|
|Appare nelle tipologie:||01 - Articolo su rivista|