Orally active, selective AP-1 transcription complex c-Fos/c-Jun inhibitor with therapeutic efficacy in a murine model of arthritis in vivo.
T-5224 is an orally active, selective AP-1 transcription complex c-Fos/c-Jun inhibitor that blocks c-Fos and c-Jun DNA-binding activity, but not that of C/EBPα, ATF-2 (bZIP domain), MyoD (bHLH domain), Sp-1 (ZF domain) and NF-κB/p65 (RHD). T-5224 inhibits PMA-induced Fos/AP-1 promoter activity (IC50 ~4 μM by NIH/3T3 reporter assay) without affectingTNFα-stimulated NF-kB activity or the cellular levels of c-Fos family protein members. T-5224 exhibits therapeutic efficacy against collagen-induced arthritis (CIA) in mice in vivo (0.3-30 mg/kg/d p.o.).
To inhibit arthritis upstream of inflammatory cytokine release and matrix metalloproteinase (MMP) action, we designed de novo a small-molecule inhibitor of c-Fos/activator protein-1 (AP-1) using three-dimensional (3D) pharmacophore modeling. This model was based on the 3D structure of the basic
FOS, a subunit of the activator protein-1 (AP-1) transcription factor, has been implicated in various cellular changes. In the human ovary, the expression of FOS and its heterodimeric binding partners JUN, JUNB, and JUND increases in periovulatory follicles. However, the
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
Previous studies have shown that expression of activator protein-1 (AP-1) family is significantly elevated in triple-negative breast cancer (TNBC), compared with that in other breast cancer subtypes. Here we investigated the anti-tumor effect and mechanism of T-5224, an inhibitor of
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