title: A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models.
abstract: 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.
authors: Cancer Research, DC0434, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. Zhao_Genshi@Lilly.com
authors: Genshi
authors: G
authors: Zhao
authors: Wei-Ying
authors: WY
authors: Li
authors: Daohong
authors: D
authors: Chen
authors: James R
authors: JR
authors: Henry
authors: Hong-Yu
authors: HY
authors: Li
authors: Zhaogen
authors: Z
authors: Chen
authors: Mohammad
authors: M
authors: Zia-Ebrahimi
authors: Laura
authors: L
authors: Bloem
authors: Yan
authors: Y
authors: Zhai
authors: Karen
authors: K
authors: Huss
authors: Sheng-Bin
authors: SB
authors: Peng
authors: Denis J
authors: DJ
authors: McCann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C570663:2-(4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol; D000970:Antineoplastic Agents; D007191:Indazoles; D017468:Receptors, Fibroblast Growth Factor