title: Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models.
abstract: Alofanib (RPT835) is a novel selective allosteric inhibitor of fibroblast growth factor receptor 2 (FGFR2). We showed previously that alofanib could bind to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced phoshphorylation of FRS2α. In the present study, we further showed that alofanib inhibited phosphorylation of FRS2α with the half maximal inhibitory concentration (IC50) values of 7 and 9 nmol/l in cancer cells expressing different FGFR2 isoforms. In a panel of four cell lines representing several tumour types (triple-negative breast cancer, melanoma, and ovarian cancer), alofanib inhibited FGF-mediated proliferation with 50% growth inhibition (GI50) values of 16-370 nmol/l. Alofanib dose dependently inhibited the proliferation and migration of human and mouse endothelial cells (GI50 11-58 nmol/l) compared with brivanib and bevacizumab. Treatment with alofanib ablated experimental FGF-induced angiogenesis in vivo. In a FGFR-driven human tumour xenograft model, oral administration of alofanib was well tolerated and resulted in potent antitumour activity. Importantly, alofanib was effective in FGFR2-expressing models. These results show that alofanib is a potent FGFR2 inhibitor and provide strong rationale for its evaluation in patients with FGFR2-driven cancers.
authors.affiliation: Ruspharmtech LLC, Saint Petersburg, Russia. Electronic address: tsimafeyeu@ruspharm.com.
authors.forename: Ilya
authors.initials: I
authors.lastname: Tsimafeyeu
authors.affiliation: Altogen Labs, Austin, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ludes-Meyers
authors.affiliation: N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Stepanova
authors.affiliation: FD Computing, Beerse, Belgium.
authors.forename: Frits
authors.initials: F
authors.lastname: Daeyaert
authors.affiliation: N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Khochenkov
authors.affiliation: EcoSynth, Oostende, Belgium.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Joose
authors.affiliation: N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Eliso
authors.initials: E
authors.lastname: Solomko
authors.affiliation: EcoSynth, Oostende, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Akene
authors.affiliation: N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Nina
authors.initials: N
authors.lastname: Peretolchina
authors.affiliation: Altogen Labs, Austin, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Oxana
authors.initials: O
authors.lastname: Ryabaya
authors.affiliation: Moscow Clinical and Research Center, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Byakhov
authors.affiliation: N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Tjulandin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001565:Benzoates; D013449:Sulfonamides; D051497:Receptor, Fibroblast Growth Factor, Type 2; C000610985:alofanib
keywords: Allosteric inhibitor; Alofanib; Fibroblast growth factor receptor 2; Preclinical studies; RPT835