“泛素-蛋白酶體”體系對(duì)細(xì)胞內(nèi)蛋白進(jìn)行標(biāo)記，以將其降解。這是很多細(xì)胞功能的調(diào)控機(jī)制的構(gòu)成部分,，其中的 一些功能與癌癥有關(guān),。
現(xiàn)在，蛋白酶體抑制因子正在成為抗腫瘤藥物,，其中第一種用于臨床的是“硼替佐米”（Bortezomib）,，用來治療多種骨髓瘤和一些淋巴瘤。
Soucy等人現(xiàn)在報(bào)告了MLN4924的發(fā)現(xiàn),，它是“NEDD8-激發(fā)酶”（NAE）的一個(gè)小分子抑制因子,，目前正在進(jìn)行一期臨床試驗(yàn)。NAE調(diào)控“泛素連接酶”一種亞型（即cullin-RING）的活性,，后者又控制各種不同細(xì)胞蛋白的降解,。MLN4924在小鼠癌癥模型中誘導(dǎo)癌細(xì)胞死亡和產(chǎn)生抗腫瘤活性。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
