title: Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia.
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. 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.
authors.affiliation: 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.
authors.forename: Ronan T
authors.initials: RT
authors.lastname: Swords
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
authors.forename: James J
authors.initials: JJ
authors.lastname: Garnsey
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.forename: Ernest
authors.initials: E
authors.lastname: Medina
authors.forename: Kelli
authors.initials: K
authors.lastname: Oberheu
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Michael
authors.initials: M
authors.lastname: O'Dwyer
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D044842:Cullin Proteins; D003517:Cyclopentanes / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D044842:Cullin Proteins; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014452:Ubiquitins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D046988:Proteasome Endopeptidase Complex; C539933:pevonedistat