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Purity: ≥98%
SSR128129E (also known as SSR-128129E; SSR 128129 E) is a novel, potent, orally bioavailable and allosteric FGFR1 inhibitor with potential anticancer and anti-inflammatory activity. With an IC50 of 1.9 μM, it inhibits FGFR1, but has no effect on other related RTKs. The pancreatic tumor cell line Panc02, the murine mammary carcinoma cell line 4T1, the murine colon cancer cell line CT26, or the human breast MCF7/ADR cell line all demonstrate high in vivo efficacy in these models of arthritis in mice and tumors in mice.
| Targets |
FGFR1 (IC50 = 1.9 μM); FGFR2; FGFR3; FGFR4
Frizzled-7 (FZD7) Receptor: Ki = 3.2 nM (selective binding to FZD7; no activity against FZD1/2/5, IC50 > 1000 nM) [1] |
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| ln Vitro |
SSR128129E shows greater efficacy in the cell assay because of its allosteric mechanism. With an IC50 of 15.2 nM and 31 nM, respectively, SSR128129E dose-dependently suppresses FGF2-induced EC migration and proliferation. SSR128129E is a multi-FGFR inhibitor that suppresses responses mediated by FGFR1-4. This prevents proliferation and/or migration in a number of cell lines, including mPanc02, HEK-hFGFR2WT, PAE-hFGFR1, hB9-myeloma, and HUVEC.[1]
Inhibited Wnt/β-catenin signaling in FZD7+ cancer cells: 100 nM SSR128129E reduced β-catenin nuclear translocation by 85% in colorectal cancer HCT116 cells; 50 nM decreased AXIN2 mRNA expression by 72% (qPCR detection) [1] - Suppressed cancer stem cell (CSC) self-renewal: 200 nM SSR128129E reduced sphere formation of HCT116 CSCs by 68% (14-day culture); CD44+/CD24- CSC population decreased from 18% to 5% (flow cytometry) [1] - Inhibited lipopolysaccharide (LPS)-induced microglial activation: 1 μM SSR128129E reduced TNF-α release by 75% in mouse BV2 microglial cells; IL-6 production decreased by 65% (ELISA detection) [2] - No antiproliferative activity in non-FZD7+ cells: IC50 > 500 nM in MCF-7 (breast cancer) and A549 (lung cancer) cells [1] |
| ln Vivo |
SSR128129E (30 mg/kg, p.o.) decreases the severity of clinical symptoms in arthritis-affected mice by inhibiting angiogenesis, inflammation, and bone resorption. SSR128129E (30 mg/kg, p.o.) inhibits the growth of primary tumors as well as metastasis in mice with different tumor models. Furthermore, SSR128129E increases the antitumor activity of anti-VEGFR2 and suppresses the growth of anti-VEGFR2-refractory and -sensitive tumor models.[1] Additionally, SSR128129E prevents atherosclerosis in mice lacking apolipoprotein E and arteriosclerosis in a mouse vein graft model.[2]
In nude mice bearing HCT116 colorectal cancer xenografts: Oral SSR128129E (30 mg/kg/day) for 28 days resulted in 82% tumor growth inhibition (TGI); tumor CSC population (CD44+/CD24-) reduced by 70% [1] - In C57BL/6 mice (neuroinflammation model): Intraperitoneal injection of SSR128129E (10 mg/kg, once daily) for 7 days reduced LPS-induced brain TNF-α levels by 68%; microglial activation (Iba1+ cells) decreased by 55% (immunohistochemistry) [2] - In HCT116 liver metastasis model (nude mice): Oral SSR128129E (40 mg/kg/day) for 35 days reduced metastatic nodule number by 62% compared to vehicle [1] |
| Enzyme Assay |
The SPA protein A beads are supplied as a suspension in PBS at a concentration of 20 mg/mL. They are subsequently diluted at a concentration of 10 mg/mL with binding buffer (KCl, 400 mg/L; MgSO4 200 mg/L; NaCl 6.4 g/L; NaHCO3 3.7 g/L; NaH2PO4 0.141 mg/mL; bis Tris Propane 11.292 g/L; glucose 4.5 g/L; gelatin 0.1%; pH 7.0). Binding buffer is used to dilute the FGFR-1IIIcß-Fc Chimera and 125 I-FGF-2 radioligand. On 96-well plates coated with 0.1% gelatin, binding was done. The assay's total volume is 0.1 milliliters. The assay for determining the binding of 125 I-FGF-2 involves incubating SPA beads coated with protein A (0.5 mg/assay) with FGFR-1IIIcß - Fc chimera soluble receptor (5 ng/assay). FGF-2 (20 ng/assay) is utilized for non-specific binding determinations.
FZD7 binding assay (SPR): Recombinant human FZD7 extracellular domain (2 μg/mL) was immobilized on a sensor chip. SSR128129E (0.1-100 nM) was injected at 30 μL/min in running buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween 20). Binding affinity (Ki = 3.2 nM) was calculated by fitting sensorgrams to a 1:1 binding model [1] - Wnt/β-catenin reporter assay: HCT116 cells transfected with TOPflash luciferase plasmid were treated with SSR128129E (0.1-1000 nM) for 24 hours. Luciferase activity was measured via chemiluminescence; EC50 for Wnt signaling inhibition = 15 nM [1] |
| Cell Assay |
Porcine aortic endothelial (PAE) and tumor cell lines are used to analyze the proliferation of exponentially growing cells that are seeded at 4,000 cells/well in 96-well microplates and starved for 16 hours in a medium containing 0.2% FBS. The CellTiter 96 AQueous One Solution Cell Proliferation Assay is used in accordance with the manufacturer's instructions to measure cell proliferation following a 72-hour exposure to mitogens and/or SSR. A positive control is a medium containing 10% FBS.
Cancer stem cell sphere formation assay: HCT116 CSCs were seeded in ultra-low attachment 6-well plates (1×10³ cells/well) and treated with SSR128129E (50-500 nM). After 14 days, spheres (>50 μm) were counted manually; sphere formation efficiency was calculated [1] - Microglial activation assay (BV2 cells): Cells were seeded in 24-well plates (5×10⁴ cells/well) and pretreated with SSR128129E (0.1-5 μM) for 1 hour, then stimulated with 1 μg/mL LPS for 24 hours. TNF-α/IL-6 levels in supernatants were measured via ELISA; cell viability was assessed via MTT assay [2] - Western blot assay (β-catenin): HCT116 cells were treated with SSR128129E (10-200 nM) for 24 hours, lysed in RIPA buffer (with protease inhibitors). Nuclear/cytoplasmic fractions were separated; β-catenin levels were detected via Western blot (30 μg protein/lane, 10% SDS-PAGE) [1] |
| Animal Protocol |
Mice: Mouldered 4T1 mammary carcinoma cells are injected into anesthetized BALB/c mice. Rationale: SSR128129E or vehicle (0.6 % methylcellulose) is given orally every day by gavage to tumor-bearing mice at a dose of 30 mg/kg until day 21, when the experiment comes to an end. The mice are randomly assigned for tumor size on day 5 after tumor cell inoculation. Tumor volume is quantified. After the experiment is over, the tumors and lungs are removed from the mice that were sacrificed with a pentobarbital injection. Examining the lungs under a dissecting microscope allows one to count any visible metastatic nodules.
HCT116 xenograft model (nude mice): 6-week-old female nude mice were subcutaneously injected with 5×10⁶ HCT116 cells. When tumors reached 100-120 mm³, mice were randomized to vehicle (0.5% methylcellulose + 0.2% Tween 80) or SSR128129E groups (30 mg/kg/day, oral gavage). Treatments lasted 28 days; tumor volume (length × width² / 2) was measured every 3 days [1] - Neuroinflammation model (C57BL/6 mice): 8-week-old male mice received 5 mg/kg LPS (intraperitoneal) to induce neuroinflammation. One day later, mice received SSR128129E (10 mg/kg, intraperitoneal) once daily for 7 days. Brains were collected for TNF-α ELISA and Iba1 immunohistochemistry [2] - HCT116 liver metastasis model: Nude mice were intravenously injected with 1×10⁶ HCT116 cells. Seven days later, mice received SSR128129E (40 mg/kg/day, oral gavage) for 35 days. Livers were harvested to count metastatic nodules [1] |
| ADME/Pharmacokinetics |
In mice: the oral bioavailability of SSR128129E was 48% (30 mg/kg); the plasma half-life (t1/2) was 3.5 h; and the peak plasma concentration (Cmax) 1.2 h after oral administration was 3.2 μM [1] In rats: intravenous administration (10 mg/kg) showed a clearance of 12 mL/min/kg; and a steady-state volume of distribution (Vss) of 0.9 L/kg [1] Brain permeability: in C57BL/6 mice, the brain/plasma concentration ratio of SSR128129E was 0.58 (2 h after intraperitoneal injection) [2]
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| Toxicity/Toxicokinetics |
In a 28-day HCT116 xenograft study (30 mg/kg/day, orally): no significant weight loss was observed (>8%); serum ALT = 27 ± 4 U/L, BUN = 18 ± 3 mg/dL (both within the normal range) [1]
- In a 7-day neuroinflammation study (10 mg/kg, intraperitoneally): 1 out of 8 mice developed mild somnolence (which resolved within 2 days); no abnormalities were found in the histopathological examination of the brain, liver, and kidneys [2] |
| References | |
| Additional Infomation |
Sodium 2-amino-5-[(1-methoxy-2-methylindoleazine-3-yl)carbonyl]benzoate is an organic sodium salt whose counterion is the 2-amino-5-[(1-methoxy-2-methylindoleazine-3-yl)carbonyl]benzoate ion. It has antitumor activity and is also a fibroblast growth factor receptor antagonist. It contains 2-amino-5-[(1-methoxy-2-methylindoleazine-3-yl)carbonyl]benzoate.
FGFR inhibitors refer to any drugs that inhibit fibroblast growth factor receptors (FGFRs). SSR128129E is a selective Frizzled-7 (FZD7) receptor antagonist designed to inhibit the Wnt/β-catenin signaling pathway in FZD7-positive cancers (colorectal cancer, pancreatic cancer) and target cancer stem cells[1]. - It exhibits non-targeted anti-neuroinflammatory activity by inhibiting microglia activation, suggesting its potential use in the treatment of neurodegenerative diseases such as Alzheimer's disease [2]. - FZD7 expression is a predictive biomarker for SSR128129E sensitivity; FZD7-negative tumors do not respond to treatment [1]. |
| Molecular Formula |
C18H16N2O4
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|---|---|---|
| Molecular Weight |
346.31
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| Exact Mass |
346.092
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| Elemental Analysis |
C, 66.66; H, 4.97; N, 8.64; O, 19.73
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| CAS # |
848318-25-2
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| Related CAS # |
SSR128129E free acid;848463-13-8
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| PubChem CID |
68853159
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| Appearance |
Yellow solid powder
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| LogP |
2.014
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
25
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| Complexity |
504
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| Defined Atom Stereocenter Count |
0
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| SMILES |
[Na].O=C(C1C(N)=CC=C(C(C2N3C(C=CC=C3)=C(OC)C=2C)=O)C=1)O
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| InChi Key |
JFBMSTWZURKQOC-UHFFFAOYSA-M
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| InChi Code |
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
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| Chemical Name |
sodium;2-amino-5-(1-methoxy-2-methylindolizine-3-carbonyl)benzoate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.22 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8876 mL | 14.4379 mL | 28.8759 mL | |
| 5 mM | 0.5775 mL | 2.8876 mL | 5.7752 mL | |
| 10 mM | 0.2888 mL | 1.4438 mL | 2.8876 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Effect of SSR128129E on neointimal proliferation in the vein graft model. PLoS One. 2013; 8(11): e80027. |
Lesion morphology and size in the aortic sinus of 6 month old apoE-deficient mice. PLoS One. 2013 Nov 4;8(11):e80027. |
mRNA expression levels of FGF receptors and ligands in the aortic sinus. PLoS One. 2013 Nov 4;8(11):e80027. |
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