T-5224

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.¹ 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.² 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.³

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1. Aikawa, Y., Morimoto, K., Yamamoto, T., et al. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat. Biotechnol. 26(7), 817-823 (2008).

2. Izuta, S., Ueki, M., Ueno, M., et al. T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice. Biotechnol. Lett. 34(12), 2175-2182 (2012).

3. Kamide, D., Yamashita, T., Araki, K., et al. Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model. Cancer Sci. 107(5), 666-673 (2016).