C25-140 is a small molecule compound that inhibits TRAF6-Ubc13 interaction. C25-140 can directly bind to the E3 ligase TNF receptor-associated factor 6 (TRAF6), thereby blocking the interaction between TRAF6 and Ubc13 and thus reducing the activity of TRAF6[1]. TRAF6 acts as a key regulator that bridges innate immunity, proinflammatory cytokines and antigen receptors to the canonical NF-κB pathway[2]. Ubc13 is a ubiquitin-conjugating enzyme E2 that also plays a key role in the activation of the NF-κB signaling pathway and plays a role in the development of inflammatory diseases and cancer[3]. C25-140 can block NF-κB activation in various immune and inflammatory signaling pathways in primary human and mouse cells[4].
In vitro, pretreatment of H9C2 cardiomyocytes with C25-140 (5μM) for 2h inhibited the expression of Bax and caspase3 in lipopolysaccharide (LPS)-induced cells and reduced the expression of Bcl2[5].
In vivo, C25-140 (5mg/kg) was intraperitoneally injected into mice with acute kidney injury (AKI) induced by diquat (DQ) poisoning for 7 days, which regulated the Toll-like receptor 4 (TLR4)/TRAF6/NF-κB signaling pathway, downregulated the levels of inflammatory cytokines IL-1β, IL-6 and TNF-α, and alleviated the symptoms of acute kidney injury in mice[6]. C25-140 (10μM, 20μM, 30μM) was intravenously injected into mice with cerebral hemorrhage, which alleviated neurological deficits after cerebral hemorrhage, reduced brain edema, and reduced the expression of pyroptotic inflammasomes such as GSDMD, NLRP3 and ASC in brain tissue[7].
References:
[1] Li J, Liu N, Tang L, et al. The relationship between TRAF6 and tumors[J]. Cancer Cell International, 2020, 20(1): 429.
[2] Häcker H, Tseng P H, Karin M. Expanding TRAF function: TRAF3 as a tri-faced immune regulator[J]. Nature Reviews Immunology, 2011, 11(7): 457-468.
[3] Zhang H, Hu H, Greeley N, et al. STAT3 restrains RANK-and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13[J]. Nature communications, 2014, 5(1): 5798.
[4] Brenke J K, Popowicz G M, Schorpp K, et al. Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity[J]. Journal of Biological Chemistry, 2018, 293(34): 13191-13203.
[5] Li Y, Zhang L, Zhang P, et al. Dehydrocorydaline protects against sepsis-induced myocardial injury through modulating the TRAF6/NF-κB pathway[J]. Frontiers in pharmacology, 2021, 12: 709604.
[6] Huang T, Rao G, Zhao Z, et al. Protective effect of tumor necrosis factor receptor-associated factor 6 inhibitor C25-140 on acute kidney injury induced by diquat poisoning in mice[J]. Zhonghua wei zhong bing ji jiu yi xue, 2024, 36(12): 1273-1278.
[7] HU Q, ZENG H, FENG C, et al. Inhibition of TRAF6 alleviates secondary brain injury by reducing neuronal pyroptosis after intracerebral hemorrhage[J]. Experimental Animals, 2024: 24-0078.