发表在《血液》上的一篇论文描述了弥漫大B细胞淋巴瘤（DLBCL）中MLN4924的新型通路调节作用机制。MLN4924是一种小分子NEDD8 -激活酶（NAE）抑制剂，而NAE是蛋白质动态平衡通路的一种关键组分。它是首个专门针对临床研究的这种酶类的小分子抑制剂，目前正在对其进行I期临床研究。
NAE调节对癌症细胞的生长和生存通路调控起关键作用的蛋白水平。其中，NAE调控NF -κB信号通路，已知其对某些类型的DLBCL的生存很重要。发表在《血液》上的论文表明，在临床前DLBCL的模型中MLN4924通过NF -κB途径抑制而表现有抗癌抗菌素活性。此外，该论文表明MLN4924还通过包括DNA再复制的其他机制而在非NF -κB依赖DLBCLs中有抗癌抗菌素活性。
“在研究论文中突出显示，在淋巴瘤（尤其是NF –κB依赖性淋巴瘤）和其他肿瘤中，MLN4924临床进展与NF –κB密切相关，”Millennium的资深科学家、论文的首席作者Peter G. Smith说。
“我们致力于实验室的创新造就了Millennium成为蛋白质平衡领域的龙头企业。MLN4924是我们引入临床的作为突破性研究成果的3种化合物之一，”Millennium 首席科学家Joseph Bolen博士说。
2009年4月Nature上发表的临床前研究数据表明，MLN4924对NAE功能的抑制改变了重要的癌症通路而导致肿瘤细胞死亡。2010年1月刊登在Molecular Cell封面文章中的临床前数据资料揭示，NAE使用MLN4924通过形成一种加成化合物或新分子、MLN4924和NAE底物NEDD8结合而生成自己的抑制剂。
生物谷推荐原文出处：
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.
