SSR128129E is an allosteric inhibitor of FGFR1 with IC50 value of 1.9 μM [1].
The fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases for fibroblast growth factors (FGFs) and play an important role in cancer and inflammation. FGF2 plays an important role in angiogenesis [1] [2].
SSR128129E is an orally-active and allosteric FGFR1 inhibitor. In human umbilical venous endothelial cells (HUVECs), SSR128129E inhibited FGF2-induced endothelial cells (ECs) proliferation and migration with IC50 values of 31 and 15.2 nM respectively and also inhibited lamellipodia formation. SSR128129E inhibited responses mediated by FGFR1-4. In FGFR2-expressing HEK293 cells, SSR128129E inhibited phosphorylation of FRS2 and ERK1/2 induced by FGF2 [1].
In arthritis mice, SSR128129E inhibited bone and joint damage and reduced angiogenesis in the inflamed joints. In orthotopic Panc02 tumor model, SSR128129E (30 mg/kg) inhibited tumor growth by 44%. In murine 4T1 breast tumors, SSR128129E (30 mg/kg) reduced tumor weight and size by 40% and 53%, respectively [1]. In atherosclerosis-prone apolipoprotein E (apoE)-deficient mice, SSR128129E (50 mg/kg) reduced neointimal proliferation and reduced FGFR2 mRNA levels and lesion size in the aortic sinus [2].
References:
[1]. Bono F, De Smet F, Herbert C, et al. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell, 2013, 23(4): 477-488.
[2]. Dol-Gleizes F, Delesque-Touchard N, Marès AM, et al. A new synthetic FGF receptor antagonist inhibits arteriosclerosis in a mouse vein graft model and atherosclerosis in apolipoprotein E-deficient mice. PLoS One, 2013, 8(11): e80027.