An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
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DOI：
10.1038/nature07884
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发表时间：
2009-04-09
期刊：
影响因子：
64.8
通讯作者：
Langston, Steven P.
中科院分区：
文献类型：
--
作者：
Soucy, Teresa A.;Smith, Peter G.;Langston, Steven P.
一种细胞蛋白酶体功能抑制剂的临床研究表明，针对泛素-蛋白酶体系统其他成分的化合物可能被证明对治疗人类恶性肿瘤有用。NEDD8激活酶(NAE)是NEDD8结合途径的重要组成部分，它控制着泛素连接酶的剔除环亚型的活性，从而调节蛋白酶体上游蛋白质的周转。Cullin环连接酶的底物在与癌细胞生长和生存途径相关的细胞过程中起着重要的作用。在这里，我们描述了MLN4924，一种有效的和选择性的NAE抑制剂。MLN4924通过一种新的作用机制，即解除对S期DNA合成的调控，扰乱了cullin环连接酶介导的蛋白质周转，导致人类肿瘤细胞的凋亡性死亡。MLN4924在耐受性良好的复合暴露下抑制小鼠体内人类肿瘤异种移植瘤的生长。我们的数据表明，NAE抑制剂可能有希望用于癌症的治疗。
The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.