Encouraged by the clinical validation of fibroblast growth factor receptor 2 (FGFR2) as the target for the treatment of several tumors, we sought to identify pharmacological agents that could target this receptor by an allosteric mechanism. We report the efficacy of RPT835, novel highly potent inhibitor of the FGFR2 extracellular domain (RusPharmTech, LLC), in vitro and in vivo.

Concordant with this activity, in human umbilical vein endothelial cells (HUVEC) and mouse endothelial cells (SVEC-4-10), RPT835 inhibited FGF-stimulated proliferation with IC50 values of 11 and 10 nmol/L, respectively. Inhibition of HUVEC cells proliferation by brivanib as positive control was significantly lower (IC50=289 nmol/L, P<0.001). Once-daily oral administration of RPT835 significantly ablated experimental FGF-induced angiogenesis in vivo and reduced endothelial cell migration, capillary-like tubular structure and mature vessel formation in comparison with bevacizumab (P<0.001). The growth of established human tumor xenograft of breast cancer (HS578T) in athymic mice was inhibited by RPT835 with chronic administration of 30 mg per kg per day. Differences with control group were significant on 34 day of study. There was no significant impact of RPT835 on colon (HCT-116, 10 mg/kg) and lung (NCI-H226, 30 mg/kg) cancer growth.

Collectively, the data obtained with RPT835 are consistent with potent inhibition of FGF signaling, angiogenesis, and breast cancer growth.

Citation Format: Ilya Tsimafeyeu, Evgenia Stepanova, Eliso Solomko, Dmitry Kochenkov, Nina Peretolchina, Oxana Ryabaya, Mikhail Byakhov, Sergey Tjulandin. Allosteric FGFR2 inhibitor RPT835 impacts on tumor growth and neovascularization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1737. doi:10.1158/1538-7445.AM2014-1737