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Ref Type Journal Article
PMID (21900693)
Authors Zhao G, Li WY, Chen D, Henry JR, Li HY, Chen Z, Zia-Ebrahimi M, Bloem L, Zhai Y, Huss K, Peng SB, McCann DJ
Title A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models.
Journal Molecular cancer therapeutics
Vol 10
Issue 11
Date 2011 Nov
URL
Abstract Text The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are present in many types of endothelial and tumor cells and play an important role in tumor cell growth, survival, and migration as well as in maintaining tumor angiogenesis. Overexpression of FGFRs or aberrant regulation of their activities has been implicated in many forms of human malignancies. Therefore, targeting FGFRs represents an attractive strategy for development of cancer treatment options by simultaneously inhibiting tumor cell growth, survival, and migration as well as tumor angiogenesis. Here, we describe a potent, selective, small-molecule FGFR inhibitor, (R)-(E)-2-(4-(2-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol, designated as LY2874455. This molecule is active against all 4 FGFRs, with a similar potency in biochemical assays. It exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma, and with a well-defined pharmacokinetic/pharmacodynamic relationship. LY2874455 also exhibits a 6- to 9-fold in vitro and in vivo selectivity on inhibition of FGF- over VEGF-mediated target signaling in mice. Furthermore, LY2874455 did not show VEGF receptor 2-mediated toxicities such as hypertension at efficacious doses. Currently, this molecule is being evaluated for its potential use in the clinic.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
LY2874455 LY2874455 6 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
LY2874455 FGFR Inhibitor (Pan) 22 LY2874455, a pan-FGFR inhibitor, has equivalent potency against FGFR1-4 and inhibits FGF/FGFR mediated signaling to reduce tumor growth (PMID: 21900693).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 over exp Advanced Solid Tumor sensitive LY2874455 Preclinical Actionable In a preclinical study, LY2874455 induced tumor regression in FGFR3-over expressing bladder and multiple myeloma xenograft models (PMID: 21900693). 21900693
FGFR3 - TACC3 urinary bladder cancer sensitive LY2874455 Preclinical Actionable In a preclinical study, LY2874455 induced tumor regression in bladder cancer xenograft models that have been demonstrated to harbor an FGFR3-TACC3 fusion (PMID: 21900693, PMID: 23175443). 21900693 23175443