T-5224

T-5224 is a non-peptidic small molecule inhibitor of c-Fos/AP-1 that specifically inhibits DNA binding activity of c-Fos/c-Jun^[1]. T-5224 regulates mast cell (MC) via a c-Fos/EGR1/IL-4 axis, reduces FcεRI-mediated MC degranulation, and diminishes EGR1 and IL-4 expression^[2]. T-5224 has been widely used to suppress inflammation and improve skin barrier function in a murine atopic dermatitis-like dermatitis^[3].

In vitro, T-5224 treatment for 24 hours notably restrained the proliferation of ARP1 cells and RPMI8226 cells, with IC₅₀ values of 9.24μM and 11.41μM, respectively^[4]. T-5224 treatment (10µM) for 24 hours significantly inhibited the IL-1β-stimulated production of MMP-1, MMP-3, IL-6, and TNFα in SW982 cells^[5]. Treatment with 80µM T-5224 for 48 hours markedly decreased the invasive activity and migratory ability of HSC-3-M3 cells and altered cell morphology^[6].

In vivo, T-5224 treatment via a single oral dose of 300mg/kg, inhibited the lipopolysaccharide (LPS)-induced increase in TNF-α levels in mouse serum and alleviated kidney damage in mice within 48 hours^[7]. Oral administration of T-5224 at a dose of 30mg/kg daily for three consecutive weeks prevented bleomycin-induced experimental skin fibrosis and reduced dermal thickening in mice^[8].

References:

[1] Ye N, Ding Y, Wild C, et al. Small molecule inhibitors targeting activator protein 1 (AP-1): Miniperspective[J]. Journal of medicinal chemistry, 2014, 57(16): 6930.

[2] Wang H N, Ji K, Zhang L N, et al. Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis[J]. Journal of translational medicine, 2021, 19(1): 261.

[3] Sasakura M, Urakami H, Tachibana K, et al. Topical application of activator protein-1 inhibitor T-5224 suppresses inflammation and improves skin barrier function in a murine atopic dermatitis-like dermatitis[J]. Allergology International, 2024, 73(2): 323-331.

[4] Tang S, Liu J, Li F, et al. AP-1 inhibitor induces ferroptosis via the PI3K/AKT pathway in multiple myeloma cells[J]. Heliyon, 2024, 10(14).

[5] Aikawa Y, Morimoto K, Yamamoto T, et al. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1[J]. Nature biotechnology, 2008, 26(7): 817-823.

[6] Kamide D, Yamashita T, Araki K, et al. Selective activator protein‐1 inhibitor T‐5224 prevents lymph node metastasis in an oral cancer model[J]. Cancer science, 2016, 107(5): 666-673.  

[7] Miyazaki H, Morishita J, Ueki M, et al. The effects of a selective inhibitor of c-Fos/activator protein-1 on endotoxin-induced acute kidney injury in mice[J]. BMC nephrology, 2012, 13(1): 153.

[8] Avouac J, Palumbo K, Tomcik M, et al. Inhibition of activator protein 1 signaling abrogates transforming growth factor β–mediated activation of fibroblasts and prevents experimental fibrosis[J]. Arthritis & Rheumatism, 2012, 64(5): 1642-1652.