1. Academic Validation
  2. Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models

Targeting FGFR2 with alofanib (RPT835) shows potent activity in tumour models

  • Eur J Cancer. 2016 Jul;61:20-8. doi: 10.1016/j.ejca.2016.03.068.
Ilya Tsimafeyeu 1 John Ludes-Meyers 2 Evgenia Stepanova 3 Frits Daeyaert 4 Dmitry Khochenkov 3 Jean-Baptiste Joose 5 Eliso Solomko 3 Koen Van Akene 5 Nina Peretolchina 3 Wei Yin 2 Oxana Ryabaya 3 Mikhail Byakhov 6 Sergei Tjulandin 3
Affiliations

Affiliations

  • 1 Ruspharmtech LLC, Saint Petersburg, Russia. Electronic address: tsimafeyeu@ruspharm.com.
  • 2 Altogen Labs, Austin, TX, USA.
  • 3 N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.
  • 4 FD Computing, Beerse, Belgium.
  • 5 EcoSynth, Oostende, Belgium.
  • 6 Moscow Clinical and Research Center, Moscow, Russia.
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.

Keywords

Allosteric inhibitor; Alofanib; Fibroblast growth factor receptor 2; Preclinical studies; RPT835.

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