title: Inhibition of RET tyrosine kinase by SU5416.
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.
authors.affiliation: Department of Clinical Medicine, Prevention and Biotechnology, University of Milan-Bicocca, Monza, Italy. luca.mologni@unimib.it
authors.forename: Luca
authors.initials: L
authors.lastname: Mologni
authors.forename: Elisa
authors.initials: E
authors.lastname: Sala
authors.forename: Sara
authors.initials: S
authors.lastname: Cazzaniga
authors.forename: Roberta
authors.initials: R
authors.lastname: Rostagno
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuoni
authors.forename: Miriam
authors.initials: M
authors.lastname: Puttini
authors.forename: Jenny
authors.initials: J
authors.lastname: Bain
authors.forename: Loredana
authors.initials: L
authors.lastname: Cleris
authors.forename: Sara
authors.initials: S
authors.lastname: Redaelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Riva
authors.forename: Franca
authors.initials: F
authors.lastname: Formelli
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D000818:Animals; D002291:Carcinoma, Papillary / Q000188:drug therapy; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007313:Insecta / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D008958:Models, Molecular; D050505:Mutant Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D013964:Thyroid Neoplasms / Q000188:drug therapy; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; C000715470:MAS1 protein, human; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011758:Pyrroles; C116890:Semaxinib; D011494:Protein Kinases; D051096:Proto-Oncogene Proteins c-ret