SCF E3 ubiquitin ligases as anticancer targets.
SCF E3 ubiquitin ligases as anticancer targets.
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DOI：
10.2174/156800911794519734
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发表时间：
2011-03
影响因子：
3
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Jia L;Sun Y
SCF （Skp1, Cullins， F-box蛋白）多亚基E3泛素连接酶，也称为CRL （Cullin-RING ubiquitin ligase）是最大的E3泛素连接酶家族，可促进各种调控蛋白的泛素化以进行靶向降解，从而调节许多生物过程，包括细胞周期进程，信号转导和DNA复制。FDA批准硼替佐米（也称为Velcade或PS-341），这是第一类（也是唯一一类）通用蛋白酶体抑制剂，用于治疗复发/难治性多发性骨髓瘤和套细胞淋巴瘤，加快了发现scf型连接酶或其成分的小分子抑制剂的努力。虽然硼替佐米已经显示出一定程度的癌细胞选择性和可测量的治疗指标，但由于其抑制整体蛋白质降解，该药物通常具有细胞毒性。另一种理想的方法是靶向特定的E3连接酶，已知在人类癌症中被激活，具有高水平的特异性和选择性，并且相关毒性较小，因为这种抑制剂可以选择性地稳定由该E3调节的特定细胞蛋白。在这里，我们回顾了最近在验证SCF E3泛素连接酶作为一个有吸引力的抗癌靶点方面的进展，并讨论了MLN4924 （nedd8激活酶的小分子抑制剂）如何通过去除cullin类化修饰来抑制SCF E3连接酶，从而开发出一类新的抗癌药物。最后，我们从未来的角度讨论了SCF生物学的基础研究将如何指导围绕这一目标的药物发现工作。
The SCF (Skp1, Cullins, F-box proteins) multisubunit E3 ubiquitin ligase, also known as CRL (Cullin-RING ubiquitin Ligase) is the largest E3 ubiquitin ligase family that promotes the ubiquitination of various regulatory proteins for targeted degradation, thus regulating many biological processes, including cell cycle progression, signal transduction, and DNA replication. The efforts to discover small molecule inhibitors of a SCF-type ligase or its components were expedited by the FDA approval of Bortezomib (also known as Velcade or PS-341), the first (and only) class of general proteasome inhibitor, for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma. Although Bortezomib has demonstrated a certain degree of cancer cell selectivity with measurable therapeutic index, the drug is, in general, cytotoxic due to its inhibition of overall protein degradation. An alternative and ideal approach is to target a specific E3 ligase, known to be activated in human cancer, for a high level of specificity and selectivity with less associated toxicity, since such inhibitors would selectively stabilize a specific set of cellular proteins regulated by this E3. Here, we review recent advances in validation of SCF E3 ubiquitin ligase as an attractive anti-cancer target and discuss how MLN4924, a small molecule inhibitor of NEDD8-activating enzyme, can be developed as a novel class of anticancer agents by inhibiting SCF E3 ligase via removal of cullin neddylation. Finally, we discuss under future perspective how basic research on SCF biology will direct the drug discovery efforts surrounding this target.
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影响因子：
16
作者：
Dehan, Elinor;Bassermann, Florian;Guardavaccaro, Daniele;Vasiliver-Shamis, Gaia;Cohen, Michael;Lowes, Kym N.;Dustin, Michael;Huang, David C. S.;Taunton, Jack;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
影响因子：
16
作者：
Brownell, James E.;Sintchak, Michael D.;Dick, Lawrence R.
通讯作者：
Dick, Lawrence R.