title: Dovitinib (CHIR258, TKI258): structure, development and preclinical and clinical activity.
abstract: Dovitinib is an oral multikinase inhibitor targeting FGF receptors, PDGF receptors and VEGF receptors. Its activity against FGF receptors suggests its usefulness in treating cancers after the failure of VEGF/VEGF receptor-targeting agents. The identified dose and schedule to be used in further studies was 500 mg orally for 5 days on and 2 days off. Biological considerations and the results achieved in a Phase I/II trial suggested its activity in advanced renal cell carcinoma patients pretreated with a tyrosine kinase inhibitor and an mTOR inhibitor. Surprisingly, in a randomized controlled Phase III trial versus sorafenib in the same setting, dovitinib failed to demonstrate any superiority. At present, dovitinib is being tested in different tumor types. However, molecular-based patient selection seems to be key to fully exploit the activity of this drug.
authors.affiliation: Medical Oncology, IRCCS San Matteo University Hospital Foundation, Piazzale C Golgi, 19, 27100 Pavia, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.forename: Palma
authors.initials: P
authors.lastname: Giglione
authors.forename: Wanda
authors.initials: W
authors.lastname: Liguigli
authors.forename: Chiara
authors.initials: C
authors.lastname: Paglino
mesh_terms: D001562:Benzimidazoles / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015363:Quinolones / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D015363:Quinolones; D017468:Receptors, Fibroblast Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: FGFR inhibitor; VEGFR inhibitor; dovitinib; drug development; renal cell carcinoma