Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics
Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics
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DOI：
10.1158/0008-5472.can-07-0568
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Weissman, Allan M.
中科院分区：
文献类型：
--
作者：
Yang, Yili;Kitagaki, Jirouta;Weissman, Allan M.
蛋白质与泛素的结合通过蛋白酶体依赖和非蛋白酶体依赖的功能发挥了许多调节作用。泛素化的改变在广泛的病理条件下被观察到，包括许多恶性肿瘤。因此，人们对靶向泛素-蛋白酶体系统治疗癌症非常感兴趣。几种阻断泛素化蛋白降解的蛋白酶体抑制剂在研究中被广泛使用，其中一种，硼替佐米，现在已在临床使用。尽管泛素激活酶（E1）具有明确的核心作用，但尚未发现El的细胞渗透性抑制剂。原则上，这些抑制剂应该阻断泛素化的所有功能。我们现在报道了4[4-（5-硝基呋喃-2-基亚甲基）-3,5-二氧基吡唑烷-1-基]-苯甲酸乙酯（PYR-41）作为第一个这样的抑制剂。出乎意料的是，除了阻断泛素化外，PYR-41还增加了细胞中的总泛素化。其分子基础尚不清楚；然而，在温度敏感的El细胞中也观察到sumo化的增加。功能上，PYR-41减弱细胞因子介导的核因子κ B活化。这与TRAF6的非蛋白酶体（Lys-63）泛素化的抑制有关，而TRAF6是I κ B激酶激活所必需的。PYR-41还能阻止下游泛素化和I κ B α的蛋白酶体降解。此外，PYR-41抑制p53的降解并激活该肿瘤抑制因子的转录活性。与此一致的是，它会不同地杀死表达p53的转化细胞。因此，PYR-41和相关的吡喃酮类化合物为差异杀伤转化细胞的能力提供了原理证明，表明了ei抑制剂作为癌症治疗药物的潜力。这些抑制剂也可以成为研究泛素化的有价值的工具。
The conjugation of proteins with ubiquitin plays numerous regulatory roles through both proteasomal-dependent and nonproteasomal-dependent functions. Alterations in ubiquitylation are observed in a wide range of pathologic conditions, including numerous malignancies. For this reason, there is great interest in targeting the ubiquitin-proteasome system in cancer. Several classes of proteasome inhibitors, which block degradation of ubiquitylated proteins, are widely used in research, and one, Bortezomib, is now in clinical use. Despite the well-defined and central role of the ubiquitin-activating enzyme (E1), no cell permeable inhibitors of El have been identified. Such inhibitors should, in principle, block all functions of ubiquitylation. We now report 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41) as the first such inhibitor. Unexpectedly, in addition to blocking ubiquitylation, PYR-41 increased total sumoylation in cells. The molecular basis for this is unknown; however, increased sumoylation was also observed in cells harboring temperature-sensitive El. Functionally, PYR-41 attenuates cytokine-mediated nuclear factor-kappa B activation. This correlates with inhibition of nonproteasomal (Lys-63) ubiquitylation of TRAF6, which is essential to I kappa B kinase activation. PYR-41 also prevents the downstream ubiquitylation and proteasomal degradation of I kappa B alpha. Furthermore, PYR-41 inhibits degradation of p53 and activates the transcriptional activity of this tumor suppressor. Consistent with this, it differentially kills transformed p53-expressing cells. Thus, PYR-41 and related pyrazones provide proof of principle for the capacity to differentially kill transformed cells, suggesting the potential for E I inhibitors as therapeutics in cancer. These inhibitors can also be valuable tools for studying ubiquitylation.