title: CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma.
abstract: The t(4;14) translocation that occurs uniquely in a subset (15%) of patients with multiple myeloma (MM) results in the ectopic expression of the receptor tyrosine kinase (RTK), fibroblast growth factor receptor 3 (FGFR3). Inhibition of activated FGFR3 in MM cells induces apoptosis, validating FGFR3 as a therapeutic target in t(4;14) MM and encouraging the clinical development of FGFR3 inhibitors for the treatment of these patients, who have a poor prognosis. We describe here the characterization of a novel, small-molecule inhibitor of class III, IV, and V RTKs, CHIR-258, as an inhibitor of FGFR3. CHIR-258 potently inhibits FGFR3 with an inhibitory concentration of 50% (IC50) of 5 nM in in vitro kinase assays and selectively inhibited the growth of B9 cells and human myeloma cell lines expressing wild-type (WT) or activated mutant FGFR3. In responsive cell lines, CHIR-258 induced cytostatic and cytotoxic effects. Importantly, addition of interleukin 6 (IL-6) or insulin growth factor 1 (IGF-1) or coculture on stroma did not confer resistance to CHIR-258. In primary myeloma cells from t(4;14) patients, CHIR-258 inhibited downstream extracellular signal-regulated kinase (ERK) 1/2 phosphorylation with an associated cytotoxic response. Finally, therapeutic efficacy of CHIR-258 was demonstrated in a xenograft mouse model of FGFR3 MM. These studies support the clinical evaluation of CHIR-258 in MM.
authors.affiliation: Department of Medical Oncology, University Health Network, Princess Margaret Hospital and McLaughlin Centre of Molecular Medicine, University of Toronto, 620 University Ave, Rm 8-204, Toronto, ON, Canada M5G 2C1. strudel@uhnres.utoronto.ca
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: Zhi Hua
authors.initials: ZH
authors.lastname: Li
authors.forename: Ellen
authors.initials: E
authors.lastname: Wei
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Christine
authors.initials: C
authors.lastname: Chen
authors.forename: Donna
authors.initials: D
authors.lastname: Reece
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003907:Dexamethasone / Q000633:toxicity; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000633:toxicity; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology; D023041:Xenograft Model Antitumor Assays
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D005938:Glucocorticoids; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D017468:Receptors, Fibroblast Growth Factor; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3