Design, synthesis, and biological evaluation of novel ubiquitin-activating enzyme inhibitors
Design, synthesis, and biological evaluation of novel ubiquitin-activating enzyme inhibitors
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DOI：
10.1016/j.bmcl.2018.03.004
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发表时间：
2018-09-01
影响因子：
2.7
通讯作者：
Suzuki, Miki
中科院分区：
文献类型：
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作者：
Itoh, Yukihiro;Suzuki, Miki
泛素激活酶是多发性骨髓瘤和乳腺癌治疗的潜在靶点，它在泛素化级联反应的初始阶段催化泛素的激活。然而，到目前为止，只有几种E1抑制剂被报道。此外，关于E1的三维结构的药物化学研究也很少。因此，在本研究中，我们试图利用基于结构的药物设计来寻找新的E1抑制剂。经过合理的设计、合成和体外生物学评价，我们确定了一种可逆的E1抑制剂(4b)。化合物4b可提高MCF-7乳腺癌细胞的P53水平，并抑制其生长。这些发现表明，可逆的E1抑制剂是潜在的抗癌药物。(C)2018爱思唯尔有限公司。保留所有权利。
Ubiquitin-activating enzyme (E1), which catalyzes the activation of ubiquitin in the initial step of the ubiquitination cascade, is a potential therapeutic target in multiple myeloma and breast cancer treatment. However, only a few E1 inhibitors have been reported to date. Moreover, there has been little medicinal chemistry research on the three-dimensional structure of E1. Therefore, in the present study, we attempted to identify novel E1 inhibitors using structure-based drug design. Following the rational design, synthesis, and in vitro biological evaluation of several such compounds, we identified a reversible E1 inhibitor (4b). Compound 4b increased p53 levels in MCF-7 breast cancer cells and inhibited their growth. These findings suggest that reversible E1 inhibitors are potential anticancer agents. (C) 2018 Elsevier Ltd. All rights reserved.