SSR128129E

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.

Tumor vasculature is regulated by FGF/FGFR signaling-mediated angiogenesis and bone marrow-derived cell recruitment: this mechanism is inhibited by SSR128129E, the first allosteric antagonist of FGFRs.[Pubmed:24760775]

J Cell Physiol. 2015 Jan;230(1):43-51.

Tumor angiogenesis is accompanied by vasculogenesis, which is involved in the differentiation and mobilization of human bone marrow cells. In order to further characterize the role of vasculogenesis in the tumor growth process, the effects of FGF2 on the differentiation of human bone marrow AC133(+) cells (BM-AC133(+)) into vascular precursors were studied in vitro. FGF2, like VEGFA, induced progenitor cell differentiation into cell types with endothelial cell characteristics. SSR128129E, a newly discovered specific FGFR antagonist acting by allosteric interaction with FGFR, abrogated FGF2-induced endothelial cell differentiation, showing that FGFR signaling is essential during this process. To assess the involvement of the FGF/FRGR signaling in vivo, the pre-clinical model of Lewis lung carcinoma (LL2) in mice was used. Subcutaneous injection of LL2 cells into mice induced an increase of circulating EPCs from peripheral blood associated with tumor growth and an increase of intra-tumoral vascular index. Treatment with the FGFR antagonist SSR128129E strongly decreased LL2 tumor growth as well as the intra-tumoral vascular index (41% and 50% decrease vs. vehicle-treated mice respectively, P < 0.01). Interestingly, SSR128129E treatment significantly decreased the number of circulating EPCs from the peripheral blood (53% inhibition vs. vehicle-treated mice, P < 0.01). These results demonstrate for the first time that the blockade of the FGF/FGFR pathway by SSR128129E reduces EPC recruitment during angiogenesis-dependent tumor growth. In this context, circulating EPCs could be a reliable surrogate marker for tumor growth and angiogenic activity.

Preclinical evidence that SSR128129E--a novel small-molecule multi-fibroblast growth factor receptor blocker--radiosensitises human glioblastoma.[Pubmed:24953334]

Eur J Cancer. 2014 Sep;50(13):2351-9.

Resistance of glioblastoma to radiotherapy is mainly due to tumour cell radioresistance, which is partially controlled by growth factors such as fibroblast growth factor (FGF). Because we have previously demonstrated the role of FGF-2 in tumour cell radioresistance, we investigate here whether inhibiting FGF-2 pathways by targeting fibroblast growth factor receptor (FGFR) may represent a new strategy to optimise the efficiency of radiotherapy in glioblastoma. Treating radioresistant U87 and SF763 glioblastoma cells with the FGFR inhibitor, SSR12819E, radiosensitises these cells while the survival after irradiation of the more radiosensitive U251 and SF767 cells was not affected. SSR128129E administration to U87 cells increases the radiation-induced mitotic cell death. It also decreased cell membrane availability of the FGFR-1 mainly expressed in these cells, increased this receptor's ubiquitylation, inhibited radiation-induced RhoB activation and modulated the level of hypoxia inducible factor, HIF-1alpha, a master regulator of hypoxia, thus suggesting a role of FGFR in the regulation of hypoxia pathways. Moreover, treating orthotopically U87 xenografted mice with SSR128129E before two subsequent local 2.5Gy irradiations significantly increased the animals neurological sign free survival (NSFS) compared to the other groups of treatment. These results strongly suggest that targeting FGFR with the FGFR blocker SSR128129E might represent an interesting strategy to improve the efficiency of radiotherapy in glioblastoma.