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].

Inhibition of RET tyrosine kinase by SU5416

MOLOGNI, LUCA;ROSTAGNO, ROBERTA;PUTTINI, MIRIAM;REDAELLI, SARA;GAMBACORTI PASSERINI, CARLO
2006-10

Abstract

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.
Articolo in rivista - Articolo scientifico
thyroid neoplasia, RET, SU5416
English
199
212
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].
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
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/545
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