Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Blood. 2010 May 6;115(18):3796-800. doi: 10.1182/blood-2009-11-254862. Epub 2010 Mar 4.
NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-kappaB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML.
NEDD8 激活酶 (NAE) 已被确定为 NEDD8 缀合途径的必需调节剂，该途径控制着许多在细胞周期进程、DNA 损伤和应激反应中具有重要作用的蛋白质的降解。在这里，我们报告了一种新型 NAE 抑制剂 MLN4924 在急性髓细胞白血病 (AML) 模型中具有很强的活性。MLN4924 诱导 AML 细胞系和原代患者标本中的细胞死亡，与 Fms 样酪氨酸激酶 3 表达和基质介导的存活信号无关，并导致关键 NAE 靶标的稳定、核因子-κB 活性的抑制、DNA 损伤和活性氧的产生。细胞氧化还原状态的破坏被证明是 MLN4924 诱导细胞凋亡的关键事件。在携带 AML 异种移植物的小鼠中给予 MLN4924 导致疾病稳定消退和 NEDDylated cullins 的抑制。我们的研究结果表明，MLN4924 是一种很有前途的新型药物，已进入 AML 治疗的临床试验。
