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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2941-2948. Prepublished online as a Blood First Edition Paper on December 14, 2004; DOI 10.1182/blood-2004-10-3913. This Article Full Text (PDF) All Versions of this Article: 2004-10-3913v1 105/7/2941    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Trudel, S. Articles by Stewart, A K Search for Related Content PubMed PubMed Citation Articles by Trudel, S. Articles by Stewart, A K Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 19, 2004 Accepted December 2, 2004 CHIR-258, a novel, multi-targeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma Suzanne Trudel*, Zhi Hua Li, Ellen Wei, Marion Wiesmann, Hong Chang, Christine Chen, Donna Reece, Carla Heise, and A K Stewart Department of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada; McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, ON, Canada Department of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada Chiron Corporation, Emeryville, CA, USA * Corresponding author; email: strudel{at}uhnres.utoronto.ca. The t(4:14) translocation that occurs uniquely in a subset (15%) of multiple myeloma (MM) patients 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 poor-prognosis patients. We describe here the characterization of a novel, small molecule inhibitor of class III-V RTKs, CHIR-258, as an inhibitor of FGFR3. CHIR-258 potently inhibits FGFR3 with 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), insulin growth factor 1 (IGF-1) or co-culture on stroma did not confer resistance to CHIR-258. In primary myeloma cells from t(4;14) patients, CHIR-258 inhibited downstream ERK1/2 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Salazar, T. Kashiwada, P. Krejci, P. Muchowski, D. Donoghue, W. R. Wilcox, and L. M. Thompson A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells Hum. Mol. Genet., June 1, 2009; 18(11): 1951 - 1961. [Abstract] [Full Text] [PDF] D. C. Tomlinson, F. R. Lamont, S. D. Shnyder, and M. A. Knowles Fibroblast Growth Factor Receptor 1 Promotes Proliferation and Survival via Activation of the Mitogen-Activated Protein Kinase Pathway in Bladder Cancer Cancer Res., June 1, 2009; 69(11): 4613 - 4620. [Abstract] [Full Text] [PDF] G. Bisping, D. Wenning, M. Kropff, D. 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