T-5224

T-5224 is a non-peptidic, small molecule and novel inhibitor of c-Fos/AP-1 [1].

T-5224 has shown the specific inhibition in a c-Fos/AP-1promoter-luciferase assay, without affecting the levels of c-Fos family protein members themselves. In addition, T-5224 has been reported to selectively inhibit the DNA binding activity of c-Fos/c-Jun, without affecting those of other transcription factors(C/EBPα and ATF-2, MyoD, Sp-1 and NF-κB/p65). Some research has been suggested that T-5224 potently suppressed the development of collagen-induced arthritis (CIA). Besides, T-5224 has been evidenced to inhibit the expression of nuclear factor of activated T-cells (NFAT) and osteoclastogenesis of the macrophage-osteoclast precursor RAW264.7cells induced by receptor activator of NF-κB ligand (RANKL). Apart from these, T-5224 has been noted to inhibit in-vitro production of the mediators (MMP-1, MMP-3, IL-6 and TNF-α) in IL-1β-stimulated human synovial SW982 cells with the mean IC50 of about 10μM. In the in vivo pharmacokinetic analysis, the ED50 of T-5224 is about 1-10mg/kg, and the Cmax is 0.03-0.5μM [1].

References:
[1] Aikawa Y1, Morimoto K, Yamamoto T, Chaki H, Hashiramoto A, Narita H, Hirono S, Shiozawa S. Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat Biotechnol. 2008 Jul;26(7):817-23.

T-5224, a selective inhibitor of c-Fos/activator protein-1, attenuates lipopolysaccharide-induced liver injury in mice.[Pubmed:22927112]

Biotechnol Lett. 2012 Dec;34(12):2175-82.

The effect of T-5224, a selective inhibitor of c-Fos/activator protein (AP)-1, on lipopolysaccharide (LPS) induced liver injury was examined in mice. Administration of LPS (10 mg kg(-1), i.p.) markedly increased serum levels of tumor necrosis factor-alpha (TNFalpha), high mobility group box 1 (HMGB1), alanine aminotransferase/aspartate aminotransferase (ALT/AST), liver tissue levels of macrophage-inflammatory protein-1 alpha (MIP-1alpha) and monocyte chemoattractant protein-1 (MCP-1), as well as hepatic necrosis and inflammation, leading to 67 % lethality. Administration of T-5224 (300 mg kg(-1), p.o.) after intraperitoneal injection of LPS imparted appreciable protection against acute elevations in serum levels of TNFalpha, HMGB1, ALT/AST as well as in liver tissue levels of MIP-1alpha and MCP-1, and reduced the lethality (27 %). These data indicate that T-5224 ameliorates liver injury and improves survival through decreasing production of proinflammatory cytokines and chemokines in endotoxemic mice.

Metabolism of the c-Fos/activator protein-1 inhibitor T-5224 by multiple human UDP-glucuronosyltransferase isoforms.[Pubmed:21346002]

Drug Metab Dispos. 2011 May;39(5):803-13.

We developed 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)me thoxy]phenyl} propionic acid (T-5224) as a novel inhibitor of the c-Fos/activator protein-1 for rheumatoid arthritis therapy. We predicted the metabolism of T-5224 in humans by using human liver microsomes (HLM), human intestinal microsomes (HIM), recombinant human cytochrome P450 (P450), and UDP-glucuronosyltransferases (UGTs). T-5224 was converted to its acyl O-glucuronide (G2) by UGT1A1 and UGT1A3 and to its hydroxyl O-glucuronide (G3) by several UGTs, but it was not metabolized by the P450s. A comparison of the intrinsic clearances (CL(int)) between HLM and HIM suggested that the glucuronidation of T-5224 occurs predominantly in the liver. UGT1A1 showed a higher k(cat)/K(m) value than UGT1A3 for G2 formation, but a lower k(cat)/K(m) value than UGT1A3 for G3 formation. A high correlation was observed between G2 formation activity and UGT1A1-specific activity (beta-estradiol 3-glucuronidation) in seven individual HLM. A high correlation was also observed between G2 formation activity and UGT1A1 content in the HLM. These results strongly suggest that UGT1A1 is responsible for G2 formation in human liver. In contrast, no such correlation was observed with G3 formation, suggesting that multiple UGT isoforms, including UGT1A1 and UGT1A3, are involved in G3 formation. G2 is also observed in rat and monkey liver microsomes as a major metabolite of T-5224, suggesting that G2 is not a human-specific metabolite. In this study, we obtained useful information on the metabolism of T-5224 for its clinical use.

T-5224, a selective inhibitor of c-Fos/activator protein-1, improves survival by inhibiting serum high mobility group box-1 in lethal lipopolysaccharide-induced acute kidney injury model.[Pubmed:26579229]

J Intensive Care. 2015 Nov 14;3:49.

BACKGROUND: Sepsis is a potentially fatal syndrome mediated by an early [e.g., tumor necrosis factor-alpha (TNF-alpha)] and late [high mobility group box-1 (HMGB-1)] proinflammatory cytokine response to infection. Sepsis-induced acute kidney injury (AKI) is associated with a high mortality. C-Fos/activator protein-1 (AP-1) controls the transactivation of proinflammatory cytokines via AP-1 binding in the promoter region. T-5224 is a de novo small molecule inhibitor of c-Fos/AP-1 that controls gene expression of multiple proinflammatory cytokines. We investigated whether T-5224, a selective inhibitor of c-Fos/AP-1, improves survival in lethal lipopolysaccharide (LPS)-induced AKI by inhibiting early (TNF-alpha) and late (HMGB-1) proinflammatory cytokine response. METHODS: Mice were divided into four groups (control, LPS, LPS + T-5224, and T-5224 only). Control mice were administered polyvinylpyrrolidone (PVP) solution orally, immediately after intraperitoneal (i.p.) saline injection. LPS mice were administered PVP solution orally immediately after i.p. LPS (10 mg/kg) injection. LPS + T-5224 mice were administered T-5224 orally (300 mg/kg) immediately after i.p. LPS injection. T-5224 mice were administered T-5224 orally (300 mg/kg) after i.p. saline injection. Serum concentrations of TNF-alpha, HMBG-1, and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay (ELISA). Serum blood urea nitrogen (BUN) and creatinine concentrations were commercially analyzed. Finally, histological examination was performed on the kidney. RESULTS: Treatment with T-5224 decreased serum TNF-alpha and HMGB-1 levels and increased survival after LPS injection. Furthermore, T-5224 treatment decreased serum BUN and creatinine concentrations but increased serum IL-10 concentration. LPS-induced pathological changes in kidney were attenuated by T-5224 treatment. CONCLUSIONS: These results suggest that T-5224, a selective inhibitor of c-Fos/AP-1, inhibits expression of early and late proinflammatory cytokines, protecting mice from LPS-induced lethality. T-5224 is a potential approach for decreasing lethality in sepsis-induced AKI.

Selective activator protein-1 inhibitor T-5224 prevents lymph node metastasis in an oral cancer model.[Pubmed:26918517]

Cancer Sci. 2016 May;107(5):666-73.

Activator protein-1 (AP-1) is a transcriptional factor that regulates the expression of various genes associated with tumor invasion and migration. The purpose of our study was to assess the therapeutic effects of a novel selective AP-1 inhibitor, T-5224, in preventing lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) in an orthotopic mouse model. We assessed the effect of T-5224 on HNSCC cell invasion, migration, proliferation, and MMP activity by carrying out an in vitro study using an invasion assay, scratch assay, WST-8 assay, and gelatin zymography. We also observed morphological changes in HNSCC cells by time-lapse microscopy. Furthermore, cervical lymph node metastasis was assessed using an orthotopic tumor model of human oral squamous cell carcinoma cells (HSC-3-M3) injected in the tongue of a BALB/c nude mouse. T-5224 (150 mg/kg) or vehicle was given orally every day for 4 weeks. Animals were killed and assessed for lymph node metastasis by H&E staining of resected lymph nodes. T-5224 significantly inhibited the invasion, migration, and MMP activity of HNSCC cells in a dose-dependent manner; there was no significant influence on cell proliferation. The antimetastatic effect of T-5224 was also confirmed in our animal study. The rate of cervical lymph node metastasis in the model was 40.0% in the T-5224-treated group (n = 30) versus 74.1% in the vehicle-treated group (n = 27; P < 0.05). In conclusion, T-5224 inhibited the invasion and migration of HNSCC cells in vitro, and prevented lymph node metastasis in head and neck cancer in an animal model.

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.

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