C25-140

C25-140 is an inhibitor of the protein-protein interaction between the E3 ligase TNF receptor-associated factor 6 (TRAF6) and ubiquitin-conjugating enzyme E2 N (Ubc13; IC₅₀ = 2.6 µM).¹ It selectively inhibits the TRAF6-Ubc13 interaction over the interactions between Ubc13-OTUB1 and Ubc13-Uev1a. C25-140 (30 µM) also selectively inhibits TRAF6-dependent ubiquitination over a panel of various E3 ligase/E2 enzymes, but does inhibit cellular inhibitor of apoptosis 1 (cIAP1) and E1/E2 enzymes in cell-free assays. It reduces IL-1β-induced activation of NF-κB in mouse embryonic fibroblasts (MEFs) when used at a concentration of 50 µM. Topical application of C25-140 (~1.5 mg/kg twice per day) reduces scaling and erythema in a mouse model of psoriasis induced by the TLR7 agonist imiquimod (Item No. 14956). It decreases disease severity in a mouse model of collagen-induced arthritis when administered at doses ranging from 6 to 14 mg/kg twice per day. C25-140 (5 mg/kg) also reduces alveolar septal thickening, pulmonary edema, and inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) in a mouse model of lung injury induced by mechanical ventilation with high tidal volumes.²

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1. Brenke, J.K., Popowicz, G.M., Schorpp, K., et al. Targeting TRAF6 E₃ ligase activity with a small-molecule inhibitor combats autoimmunity. The Journal of Biological Chemisty 293(34), 13191-13203 (2018).

2. Zeng, Q., Ye, L., Ling, M., et al. TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model. Int. Immunopharmacol. 96:107774, (2021).