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.
C25-140是一种能够抑制TRAF6-Ubc13相互作用的小分子化合物，能够直接与E3连接酶TNF受体相关因子6（TRAF6）结合，从而阻断TRAF6与Ubc13的相互作用，并因此降低TRAF6的活性[1]。TRAF6充当将先天免疫、促炎细胞因子和抗原受体桥接到典型NF-κB通路的关键调节因子[2]。Ubc13是一种泛素偶联酶E2，在NF-κB信号通路的激活中也起着关键作用，并在炎症性疾病和癌症的发展中发挥作用[3]。C25-140能够阻碍原代人类和小鼠细胞中各种免疫和炎症信号通路中NF-κB活化[4]。
在体外，C25-140（5μM）预处理H9C2心肌细胞2h，抑制了脂多糖（LPS）诱导的细胞中的Bax和caspase3表达，并降低了Bcl2的表达[5]。
在体内，C25-140（5mg/kg）通过腹腔注射治疗敌草快（DQ）中毒诱导的急性肾损伤（AKI）小鼠7天，调节了Toll样受体4（TLR4）/TRAF6/NF-κB信号通路，下调了炎症细胞因子IL-1β、IL-6和TNF-α水平，缓解了小鼠的急性肾损伤症状[6]。C25-140（10μM, 20μM, 30μM）通过静脉注射治疗脑出血小鼠，减轻了脑出血后的神经功能缺损，减少脑水肿，降低了脑组织中GSDMD、NLRP3和ASC等细胞焦亡炎症小体的表达[7]。