Inhibition of RET tyrosine kinase by SU5416.
J Mol Endocrinol
; 37(2): 199-212, 2006 Oct.
Article
em En
| MEDLINE
| ID: mdl-17032739
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirróis
/
Inibidores de Proteínas Quinases
/
Proteínas Proto-Oncogênicas c-ret
/
Indóis
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Mol Endocrinol
Ano de publicação:
2006
Tipo de documento:
Article