Inhibition of nedd8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia
Swords, R. T.
Kelly, K. R.
Smith, P. G.
Garnsey, J. J.
Nawrocki, S. T.
Giles, F. J.
Carew, J. S.
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Swords, R. T. Kelly, K. R.; Smith, P. G.; Garnsey, J. J.; Mahalingam, D.; Medina, E.; Oberheu, K.; Padmanabhan, S.; O'Dwyer, M.; Nawrocki, S. T.; Giles, F. J.; Carew, J. S. (2010). Inhibition of nedd8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood 115 (18), 3796-3800
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-kappa B 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 NEDDy-lated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML. (Blood. 2010; 115(18):3796-3800)