SMER 3 is a small-molecule compound that selectively inhibits the SCFMet30 ubiquitin E3 ligase. By directly binding to the F-box protein Met30, SMER 3 disrupts the interaction between Met30 and Skp1, thereby specifically inhibiting the activity of the SCFMet30 ubiquitin ligase without affecting the function of other SCF complexes, such as SCFCdc4[1].
In vitro, pretreatment of HeLa, A549, and HT-29 cells with SMER 3 (2.5–50μM) for 24 hours significantly enhances oxidative stress and induces cell death in cancer cells by promoting hydrogen peroxide (H₂O₂) accumulation and mitochondrial dysfunction[2]. Treatment of human umbilical vein endothelial cells (HUVECs) with SMER 3 (0.1–1μM) for 3–6 hours specifically inhibits the activity of SCF-family E3 ubiquitin ligases, markedly increasing the stability of the glycolytic key protein PFKFB3 and reducing its ubiquitination level[3].
References:
[1] Aghajan M, Jonai N, Flick K, et al. Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase. Nat Biotechnol. 2010 Jul;28(7):738-42.
[2] Hao Y, Langford TF, Moon SJ, et al. Screening compound libraries for H2O2-mediated cancer therapeutics using a peroxiredoxin-based sensor. Cell Chem Biol. 2022 Apr 21;29(4):625-635.e3.
[3] Boscaro C, Carotti M, Albiero M, et al. Non-genomic mechanisms in the estrogen regulation of glycolytic protein levels in endothelial cells. FASEB J. 2020 Sep;34(9):12768-12784.
SMER 3是一种选择性抑制SCFMet30泛素E3连接酶的小分子化合物。SMER 3通过直接结合F-box蛋白Met30，破坏Met30与Skp1的相互作用，从而特异性抑制SCFMet30泛素连接酶的活性，但并不影响其他SCF复合物如SCFCdc4的功能[1]。
在体外，SMER 3（2.5-50μM）预处理HeLa细胞、A549细胞及HT-29细胞24小时，通过诱导过氧化氢（H₂O₂）积累和线粒体功能障碍，显著增强癌细胞氧化应激并诱导细胞死亡[2]。SMER 3（0.1-1μM）处理人脐静脉内皮细胞（HUVECs）3-6小时，通过特异性抑制SCF家族E3泛素连接酶的活性，显著增加糖酵解关键蛋白PFKFB3的稳定性并降低其泛素化水平[3]。