Pevonedistat (<scp>MLN</scp>4924), a First‐in‐Class <scp>NEDD</scp>8‐activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

Swords, Ronan; Erba, Harry P.; DeAngelo, Daniel J.; Bixby, Dale; Altman, Jessica K.; Maris, Michael B.; Hua, Zhaowei; Blakemore, Stephen J.; Faessel, Hélène M.; Sedarati, Farhad; Dezube, Bruce J.; Giles, Francis J.; Medeiros, Bruno C.

doi:10.1111/bjh.13323

Cited by 213 publications

(214 citation statements)

References 49 publications

(73 reference statements)

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“…Indeed, MLN4924 has successfully passed through preclinical tests and is under evaluation for clinical stages. 36,37 A phase 1 study has been done on patients with acute myeloid leukemia and myelodysplastic syndromes. The patients were treated with a 60-min intravenous infusion of MLN4924 according to two different administration schedules, which were repeated every 21 days.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the patients' responses, the maximum tolerated dose (MTD) of MLN4924 was finally determined as either 59 or 83 mg/m 2 in two cohorts. 37 However, as MLN4924 has been tested as an anticancer drug, the tolerable upper limit of toxicity may be higher than that of developing anti-obesity drugs. This is why we treated mice with MLN4924 at a lower dose.…”

Section: Discussionmentioning

confidence: 99%

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PPARγ neddylation essential for adipogenesis is a potential target for treating obesity

Park

et al. 2016

Cell Death Differ

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The preadipocyte-to-adipocyte differentiation (adipogenesis) is a key process in fat mass increase and thus it is regarded as a compelling target for preventing or treating obesity. Of adipogenic hormone receptors, peroxisome proliferator-activated receptor gamma (PPARγ) has crucial roles in adipogenesis and lipid accumulation within adipocytes. Here we demonstrate that the NEDD8 (neuronal precursor cell expressed, developmentally downregulated 8)-based post-translation modification (neddylation) of PPARγ is essential for adipogenesis. During adipogenesis, NEDD8 is robustly induced in preadipocytes and conjugates with PPARγ, leading to PPARγ stabilization. When the neddylation process was blocked by NEDD8-targeting siRNAs (or viral vectors) or an inhibitor MLN4924, adipocyte differentiation and fat tissue development were substantially impaired. We also demonstrate that MLN4924 effectively prevents the high-fat diet-induced obesity and glucose intolerance in mice. This study provides a better understanding of how the PPARγ signaling pathway starts and lasts during adipogenesis and a potential anti-obesity strategy that targets the neddylation of PPARγ.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PPARγ neddylation essential for adipogenesis is a potential target for treating obesity

Park

et al. 2016

Cell Death Differ

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“…Preliminary reports from a Phase I clinical trial of MLN4924 in AML have indicated benefit in patients with difficult to treat relapsed and refractory disease. 4 As clinical development of MLN4924 in myeloid malignancies continues (www.clinicaltrials.gov), these promising results provide the impetus for determining the mechanism of MLN4924-induced cytotoxicity downstream of NAE inhibition, understanding possible mechanisms of MLN4924 resistance in AML, and assessing possible strategies for combining MLN4924 with other agents that have activity in hematological malignancies.…”

Section: Discussionmentioning

confidence: 99%

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors

et al. 2015

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MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

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“…36 Pevonedistat has been evaluated in patients with relapsed/refractory AML or myelodysplastic syndrome. 37 Two dose schedules were tested among 53 patients: pevonedistat was administered at escalating doses For personal use only. on May 12, 2018.…”

Section: Discussionmentioning

confidence: 99%

Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo

Czuczman

Barth

Gu³

et al. 2016

Blood

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Key Points• Pevonedistat (MLN4924), a NEDD8-activating enzyme inhibitor, is active in MCL preclinical models and potentiates rituximab activity.• Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 mM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-kB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-kB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL. (Blood. 2016;127(9):1128-1137

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Pevonedistat (MLN4924), a First‐in‐Class NEDD8‐activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

Cited by 213 publications

References 49 publications

PPARγ neddylation essential for adipogenesis is a potential target for treating obesity

PPARγ neddylation essential for adipogenesis is a potential target for treating obesity

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors

Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo

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