“泛素-蛋白酶体”体系对细胞内蛋白进行标记，以将其降解。这是很多细胞功能的调控机制的构成部分，其中的 一些功能与癌症有关。
现在，蛋白酶体抑制因子正在成为抗肿瘤药物，其中第一种用于临床的是“硼替佐米”（Bortezomib），用来治疗多种骨髓瘤和一些淋巴瘤。
Soucy等人现在报告了MLN4924的发现，它是“NEDD8-激发酶”（NAE）的一个小分子抑制因子，目前正在进行一期临床试验。NAE调控“泛素连接酶”一种亚型（即cullin-RING）的活性，后者又控制各种不同细胞蛋白的降解。MLN4924在小鼠癌症模型中诱导癌细胞死亡和产生抗肿瘤活性。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 458, 732-736 (9 April 2009) | doi:10.1038/nature07884
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Teresa A. Soucy1, Peter G. Smith1, Michael A. Milhollen1, Allison J. Berger1, James M. Gavin1, Sharmila Adhikari1, James E. Brownell1, Kristine E. Burke1, David P. Cardin1, Stephen Critchley1, Courtney A. Cullis1, Amanda Doucette1, James J. Garnsey1, Jeffrey L. Gaulin1, Rachel E. Gershman1, Anna R. Lublinsky1, Alice McDonald1, Hirotake Mizutani1, Usha Narayanan1, Edward J. Olhava1, Stephane Peluso1, Mansoureh Rezaei1, Michael D. Sintchak1, Tina Talreja1, Michael P. Thomas1, Tary Traore1, Stepan Vyskocil1, Gabriel S. Weatherhead1, Jie Yu1, Julie Zhang1, Lawrence R. Dick1, Christopher F. Claiborne1, Mark Rolfe1, Joseph B. Bolen1 & Steven P. Langston1
1 Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Top of pageAbstractThe 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.
