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T-5224

MCE China：T-5224

Brand：MedChemExpress (MCE)

Cat. No.HY-12270

CAS：530141-72-1

Purity：99.18%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：T-5224 is a transcription factor c-Fos/activator protein (AP)-1 inhibitor with anti-inflammatory effects, which specifically inhibits the DNA binding activity of c-Fos/c-Jun without affecting other transcription factors. T-5224 inhibits the IL-1β-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription.

In Vitro：T-5224 inhibits in-vitro production of the mediators MMP-1, MMP-3, IL-6 and TNF-α by IL-1β-stimulated human synovial SW982 cells with the mean IC50 of about 10 μM[2]. T-5224 (0-80 μM) significantly inhibits the invasion, migration, and MMP activity of HSC-3-M3 cells in a dose-dependent manner[3].

In Vivo：Administration of T-5224 (300 mg/kg, p.o.) after intraperitoneal injection of LPS impartes appreciable protection against acute elevations in serum levels of TNFα, HMGB1, ALT/AST as well as in liver tissue levels of MIP-1α and MCP-1, and reduces the lethality (27%)[4]. G2 is observed in rat and monkey liver microsomes as a major metabolite of T-5224, suggesting that G2 is not a human-specific metabolite[5]. T-5224 (300 mg/kg, p.o.) inhibits the production of TNF-alpha and other downstream effectors in C57BL/6 mice[6].

Animal Administration：Mice in LPS group are administered orally with polyvinylpyrrolidone solution in the same volume of T-5224 solution immediately after LPS injection, while in the T-5224 group, mice are administered orally with T-5224 (300 mg/kg, p.o.) in the same manner. In the control group, mice receives polyvinylpyrrolidone solution orally soon after intraperitoneal saline injection. Blood samples are collected for each measurement at the optimal time.

Cell Assay：HSC-3-M3 cells are starved for 24 h with DMEM containing 0.5% FBS. The top chamber of the cell invasion device is coated with 50 μL of 0.1 × basement membrane extract solution and incubataed overnight. HSC-3-M3 cells (5.0 × 104 cells/well) are added to the top chamber with DMEM containing 0.5% FBS mixed with 0-80 μM T-5224; DMEM with 10% FBS is added to the bottom chamber and incubated for 48 h. The bottom plate is read using a multilabel plate reader. The data are compared with the standard curve to determine the fraction of invaded cells.

IC50 & Target：c-Fos

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References：

[1]. Makino H, et al. A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebraldisc degeneration and associated pain. Sci Rep. 2017 Dec 5;7(1):16983.  [Content Brief]

[2]. Aikawa Y, et al. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotechnol. 2008 Jul;26(7):817-23.  [Content Brief]

[3]. Kamide D, et al. Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model. Cancer Sci.?2016 May;107(5):666-73.  [Content Brief]

[4]. Izuta S, et al. T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice. Biotechnol Lett. 2012 Dec;34(12):2175-82.  [Content Brief]

[5]. Uchihashi S, et al. Metabolism of the c-Fos/activator protein-1 inhibitor T-5224 by multiple human UDP-glucuronosyltransferase isoforms. Drug Metab Dispos. 2011 May;39(5):803-13.  [Content Brief]

[6]. Miyazaki H, et al. The effects of a selective inhibitor of c-Fos/activator protein-1 on endotoxin-induced acute kidney injury in mice. BMC Nephrol. 2012 Nov 23;13:153.  [Content Brief]