| Description |
T-5224 is a selective inhibitor of c-Fos/activator protein (AP)-1. It also inhibits MMP3/13 with IC50s of 10 nM.
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| Related Catalog |
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| Target |
IC50: 10 nM (MMP-3), 10 nM (MMP-13)
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| In Vitro |
T-5224 (0-80 μM) significantly inhibits the invasion, migration, and MMP activity of HSC-3-M3 cells in a dose-dependent manner. There is no significant influence on HSC-3-M3 amd OSC-19 cells proliferation[4].
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| In Vivo |
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[1]. T-5224 (300 mg/kg, p.o.) inhibits the production of TNF-alpha and other downstream effectors in C57BL/6 mice[2]. 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%)[3].
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| 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.
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| Animal Admin |
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.
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| References |
[1]. 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. [2]. 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. [3]. 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. [4]. 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. [5]. Zeng H, et al. An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery. Cell Stem Cell. 2016 Sep 1;19(3):326-40. [6]. Mukherjee A, et al. Infralimbic cortex is required for learning alternatives to prelimbic promoted associations through reciprocal connectivity. Nat Commun. 2018 Jul 13;9(1):2727.
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