發(fā)表在《血液》上的一篇論文描述了彌漫大B細(xì)胞淋巴瘤（DLBCL）中MLN4924的新型通路調(diào)節(jié)作用機(jī)制,。MLN4924是一種小分子NEDD8 -激活酶（NAE）抑制劑，而NAE是蛋白質(zhì)動態(tài)平衡通路的一種關(guān)鍵組分,。它是首個專門針對臨床研究的這種酶類的小分子抑制劑,，目前正在對其進(jìn)行I期臨床研究。
NAE調(diào)節(jié)對癌癥細(xì)胞的生長和生存通路調(diào)控起關(guān)鍵作用的蛋白水平,。其中,，NAE調(diào)控NF -κB信號通路，已知其對某些類型的DLBCL的生存很重要,。發(fā)表在《血液》上的論文表明,，在臨床前DLBCL的模型中MLN4924通過NF -κB途徑抑制而表現(xiàn)有抗癌抗菌素活性。此外,，該論文表明MLN4924還通過包括DNA再復(fù)制的其他機(jī)制而在非NF -κB依賴DLBCLs中有抗癌抗菌素活性,。
“在研究論文中突出顯示，在淋巴瘤（尤其是NF –κB依賴性淋巴瘤）和其他腫瘤中,，MLN4924臨床進(jìn)展與NF –κB密切相關(guān),，”Millennium的資深科學(xué)家、論文的首席作者Peter G. Smith說。
“我們致力于實(shí)驗(yàn)室的創(chuàng)新造就了Millennium成為蛋白質(zhì)平衡領(lǐng)域的龍頭企業(yè),。MLN4924是我們引入臨床的作為突破性研究成果的3種化合物之一,，”Millennium 首席科學(xué)家Joseph Bolen博士說。
2009年4月Nature上發(fā)表的臨床前研究數(shù)據(jù)表明,，MLN4924對NAE功能的抑制改變了重要的癌癥通路而導(dǎo)致腫瘤細(xì)胞死亡,。2010年1月刊登在Molecular Cell封面文章中的臨床前數(shù)據(jù)資料揭示，NAE使用MLN4924通過形成一種加成化合物或新分子,、MLN4924和NAE底物NEDD8結(jié)合而生成自己的抑制劑,。
生物谷推薦原文出處：
Blood, DOI 10.1182/blood-2010-03-272567.
MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-B–dependent lymphoma
Michael A. Milhollen1,*, Tary Traore1,*, Jennifer Adams-Duffy1, Michael P. Thomas1, Allison J. Berger1, Lenny Dang1, Lawrence R. Dick1, James J. Garnsey1, Erik Koenig1, Steven P. Langston1, Mark Manfredi1, Usha Narayanan1, Mark Rolfe1, Louis M. Staudt2, Teresa A. Soucy1, Jie Yu1, Julie Zhang1, Joseph B. Bolen1, and Peter G. Smith1
MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell–like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pIB, decrease in nuclear p65 content, reduction of nuclear factor-B (NF-B) transcriptional activity, and G1 arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-B pathway inhibition. Treatment of germinal-center B cell–like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-B pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NF-B pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-B–dependent lymphomas.
