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. 2010 May 6;115(18):3796-800.
doi: 10.1182/blood-2009-11-254862. Epub 2010 Mar 4.

Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia (VSports注册入口)

Ronan T Swords  1 , Kevin R Kelly, Peter G Smith, James J Garnsey, Devalingam Mahalingam, Ernest Medina, Kelli Oberheu, Swaminathan Padmanabhan, Michael O'Dwyer, Steffan T Nawrocki, Francis J Giles, Jennifer S Carew
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Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia

Ronan T Swords et al. Blood. .
Free article

Abstract

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 VSports手机版. 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. .

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