title: Potent, selective inhibitors of fibroblast growth factor receptor define fibroblast growth factor dependence in preclinical cancer models.
abstract: We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Squires
authors.forename: George
authors.initials: G
authors.lastname: Ward
authors.forename: Gordan
authors.initials: G
authors.lastname: Saxty
authors.forename: Valerio
authors.initials: V
authors.lastname: Berdini
authors.forename: Anne
authors.initials: A
authors.lastname: Cleasby
authors.forename: Peter
authors.initials: P
authors.lastname: King
authors.forename: Patrick
authors.initials: P
authors.lastname: Angibaud
authors.forename: Tim
authors.initials: T
authors.lastname: Perera
authors.forename: Lynsey
authors.initials: L
authors.lastname: Fazal
authors.forename: Douglas
authors.initials: D
authors.lastname: Ross
authors.forename: Charlotte Griffiths
authors.initials: CG
authors.lastname: Jones
authors.forename: Andrew
authors.initials: A
authors.lastname: Madin
authors.forename: Rajdeep K
authors.initials: RK
authors.lastname: Benning
authors.forename: Emma
authors.initials: E
authors.lastname: Vickerstaffe
authors.forename: Alistair
authors.initials: A
authors.lastname: O'Brien
authors.forename: Martyn
authors.initials: M
authors.lastname: Frederickson
authors.forename: Michael
authors.initials: M
authors.lastname: Reader
authors.forename: Christopher
authors.initials: C
authors.lastname: Hamlett
authors.forename: Michael A
authors.initials: MA
authors.lastname: Batey
authors.forename: Sharna
authors.initials: S
authors.lastname: Rich
authors.forename: Maria
authors.initials: M
authors.lastname: Carr
authors.forename: Darcey
authors.initials: D
authors.lastname: Miller
authors.forename: Ruth
authors.initials: R
authors.lastname: Feltell
authors.forename: Abarna
authors.initials: A
authors.lastname: Thiru
authors.forename: Susanne
authors.initials: S
authors.lastname: Bethell
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Devine
authors.forename: Brent L
authors.initials: BL
authors.lastname: Graham
authors.forename: Andrew
authors.initials: A
authors.lastname: Pike
authors.forename: Jose
authors.initials: J
authors.lastname: Cosme
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lewis
authors.forename: Eddy
authors.initials: E
authors.lastname: Freyne
authors.forename: John
authors.initials: J
authors.lastname: Lyons
authors.forename: Julie
authors.initials: J
authors.lastname: Irving
authors.forename: Christopher
authors.initials: C
authors.lastname: Murray
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Neil T
authors.initials: NT
authors.lastname: Thompson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors