SSR128129E

SSR128129E (SSR) is an potent FGFR inhibitor, which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR128129E exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR128129E is highly conserved throughout the animal kingdom. Oral delivery of SSR128129E inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.

Product information

CAS Number: 848318-25-2

Molecular Weight: 346.31

Formula: C18H15N2NaO4

Synonym:

SSR128129E

SSR 128129E

SSR-128129E

Chemical Name: sodium 2-amino-5-(1-methoxy-2-methylindolizine-3-carbonyl)benzoate

Smiles: [Na+].CC1C(OC)=C2C=CC=CN2C=1C(=O)C1=CC(C([O-])=O)=C(N)C=C1

InChiKey: JFBMSTWZURKQOC-UHFFFAOYSA-M

InChi: InChI=1S/C18H16N2O4.Na/c1-10-15(20-8-4-3-5-14(20)17(10)24-2)16(21)11-6-7-13(19)12(9-11)18(22)23;/h3-9H,19H2,1-2H3,(H,22,23);/q;+1/p-1

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Solubility (25°C) DMSO: 69 mg/mL(199.24 mM). Water: 1 mg/mL(2.88 mM).

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

SSR128129E inhibits FGF2-induced EC proliferation with an IC50 of 31±1.6 nM, migration with an IC50 of 15.2±4.5 nM, and lamellipodia formation in a dose dependent manner. SSR128129E inhibits responses mediated by FGFR1-4. For instance, SSR128129E blocks EC migration in response to FGF1, a ligand of FGFR1 and FGFR4, and capillary tube formation in response to FGF19, a ligand of FGFR4. Proliferation and migration of the murine pancreatic Panc02 tumor cell line in response to FGF7 are also blocked by SSR128129E, showing that SSR128129E inhibits FGFR subtypes of other species as well. SSR128129E blocks different FGFR subtypes in various cell lines with nanomolar potency.

In Vivo:

Oral delivery of SSR128129E (30 mg/kg/day, from day 3) inhibits growth of orthotopic Panc02 tumors by 44% and delays growth of Lewis lung carcinoma. oral SSR128129E (30 mg/kg/day, from day 5) reduces tumor size and weight by 53% and 40%, respectively. SSR128129E inhibits the growth of subcutaneous CT26 colon tumors by 34% and of the multidrug resistant MCF7/ADR breast cancer xenograft model by 40%. SSR128129E reduces tumor invasiveness and metastasis of Panc02 tumor cells to peritoneal lymph nodes.

References:

1. Dol-Gleizes F, Delesque-Touchard N, Marès AM, Nestor AL, Schaeffer P, Bono F. A New Synthetic FGF Receptor Antagonist Inhibits Arteriosclerosis in a Mouse Vein Graft Model and Atherosclerosis in Apolipoprotein E-Deficient Mice. PLoS One. 2013 Nov 4;8(11):e80027. doi: 10.1371/journal.pone.0080027. PubMed PMID: 24224032; PubMed Central PMCID: PMC3817113.
2. Herbert C, Alcouffe C, Bono F. [SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling]. Med Sci (Paris). 2013 Oct;29(10):834-6. doi: 10.1051/medsci/20132910007. Epub 2013 Oct 18. French. PubMed PMID: 24148118.
3. Herbert C, Schieborr U, Saxena K, Juraszek J, De Smet F, Alcouffe C, Bianciotto M, Saladino G, Sibrac D, Kudlinzki D, Sreeramulu S, Brown A, Rigon P, Herault JP, Lassalle G, Blundell TL, Rousseau F, Gils A, Schymkowitz J, Tompa P, Herbert JM, Carmeliet P, Gervasio FL, Schwalbe H, Bono F. Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell. 2013 Apr 15;23(4):489-501. doi: 10.1016/j.ccr.2013.02.018. PubMed PMID: 23597563.
4. Bono F, De Smet F, Herbert C, De Bock K, Georgiadou M, Fons P, Tjwa M, Alcouffe C, Ny A, Bianciotto M, Jonckx B, Murakami M, Lanahan AA, Michielsen C, Sibrac D, Dol-Gleizes F, Mazzone M, Zacchigna S, Herault JP, Fischer C, Rigon P, Ruiz de Almodovar C, Claes F, Blanc I, Poesen K, Zhang J, Segura I, Gueguen G, Bordes MF, Lambrechts D, Broussy R, van de Wouwer M, Michaux C, Shimada T, Jean I, Blacher S, Noel A, Motte P, Rom E, Rakic JM, Katsuma S, Schaeffer P, Yayon A, Van Schepdael A, Schwalbe H, Gervasio FL, Carmeliet G, Rozensky J, Dewerchin M, Simons M, Christopoulos A, Herbert JM, Carmeliet P. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell. 2013 Apr 15;23(4):477-88. doi: 10.1016/j.ccr.2013.02.019. PubMed PMID: 23597562.
5. Mohan SK, Rani SG, Chiu IM, Yu C. WITHDRAWN: Interaction of FGF1 with a novel anti-angiogenic drug SSR128129E. Arch Biochem Biophys. 2012 Jun 5. [Epub ahead of print] PubMed PMID: 22683470.

Products are for research use only. Not for human use.