C25-140

C25-140, a first-in-class TRAF6-Ubc13 inhibitor, directly binds to TRAF6, thereby blocks the interaction of TRAF6 with Ubc13 and as a consequence lowers TRAF6 activity. C25-140 expands studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis (RA)[1].

Signaling Pathways >> Metabolic Enzyme/Protease >> E1/E2/E3 Enzyme

Research Areas >> Inflammation/Immunology

Signaling Pathways >> Apoptosis >> TNF Receptor

TRAF6-Ubc13[1]

C25-140 dose-dependently impedes TRAF6-Ubc13 interaction[1]. C25-140 (10-30 μM; 2 hours) effectively reduces TRAF6-mediated ubiquitin chain formation[1]. C25-140 affects TNFα-induced phosphorylation of IκBα as well as NF-κB-induced target gene expression[1]. C25-140 efficiently inhibits IL-1β- and TNFα-mediated receptor signaling in the context of cytokine activation[1]. Western Blot Analysis[1] Cell Line: TRAF6WT Concentration: 10 μM, 20 μM, 30 μM Incubation Time: 2 hours Result: Effectively reduced TRAF6-mediated ubiquitin chain formation.

C25-140 (~1.5 mg/kg; topically to the shaved back and the right ear; twice daily for 6 days) ameliorates symptoms of autoimmune psoriasis in Imiquimod-induced psoriasis mouse model[1]. C25-140 (6-14 mg/kg; given i.p.; twice daily for 14 days) shows a dose-dependent improvement of RA disease outcome in Collagen-induced arthritis (CIA) model[1]. Animal Model: Imiquimod-induced psoriasis mouse model (male BALB/c mice)[1] Dosage: ~1.5 mg/kg Administration: Topically to the shaved back and the right ear; twice daily for 6 days Result: Showed a dose-dependent improvement of RA disease outcome. Animal Model: Collagen-induced arthritis (CIA) model in DBA1/J mice[1] Dosage: 6 mg/kg, 10 mg/kg, 14 mg/kg Administration: Given i.p.; twice daily for 14 days Result: Ameliorated the arthritic index to almost baseline levels in this efficacy model at doses of 10 and 14 mg/kg. Dose-dependently improved symptoms of RA including inflammation and structural damage.

[1]. Brenke JK, et al. Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity. J Biol Chem. 2018 Aug 24;293(34):13191-13203.