Description
T-5224 is an inhibitor of c-fos/activator protein 1 (AP-1). It inhibits the DNA binding activity of c-fos/AP-1 without affecting the activity of C/EBPα, ATF2, MyoD, Sp1, and NF-κB/p65
in vitro. It shows inhibitory activity in a c-fos/AP-1 promoter luciferase assay without changing c-fos family protein expression levels in TNF-α-stimulated NIH/3T3 cells. Administration of T-5224 (30 mg/kg) inhibits the development of collagen-induced arthritis in mice through reduction of IL-1β production, neutrophil infiltration, and synovial cell proliferation. It reduces the inflammatory cytokine response in LPS-challenged mice, lowering levels of TNF-α and HMGB1 in the serum and MIP-1α and MCP-1 in the liver. T-5224 reduces
in vivo necrosis of liver tissue and improves survival rates in LPS-challenged mice. T-5224 also exhibits anticancer activity, reducing proliferation and migration of HSC-3-M3 head and neck squamous carcinoma cells
in vitro and the number of metastases in an HSC-3-M3 orthotopic xenograft model
in vivo.
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].
References
[1] YUKIHIKO AIKAWA. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1[J]. Nature biotechnology, 2008, 26 7: 817-823. DOI:
10.1038/nbt1412[2] SHINICHIRO IZUTA. T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice.[J]. Biotechnology Letters, 2012, 34 12: 2175-2182. DOI:
10.1007/s10529-012-1022-4[3] DAISUKE KAMIDE. Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model[J]. Cancer Science, 2016, 107 5: 666-673. DOI:
10.1111/cas.12914
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