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

Published:3 March 2016 DOI: 10.1182/blood-2015-04-640920 PMID: 26675347
Natalie M Czuczman,?Matthew J Barth,?Juan Gu,?Vishala Neppalli,?Cory Mavis,?Sarah E Frys,?Qiang Hu,?Song Liu,?Pavel Klener,?Petra Vockova,?Myron S Czuczman,?Francisco J Hernandez-Ilizaliturri

Abstract

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 μM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-κB 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-κB 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.

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Related products
Procduct Name CAS Molecular Formula Supplier Price
Cytarabine 147-94-4 C9H13N3O5 706 suppliers $5.00-$1025.00
Pevonedistat 905579-51-3 C21H25N5O4S 153 suppliers $49.00-$4735.50
Rituximab 174722-31-7 C6416H9874N1688O1987S44 100 suppliers Inquiry
Bendamustine 97832-05-8 C16H21Cl2N3O2.HCl 40 suppliers Inquiry
JEKO-1 human mantle cell lymphoma cells 33 suppliers Inquiry
Bcl-XL 19 suppliers Inquiry
Ubiquitin-activating enzyme E1C 8 suppliers Inquiry
THP1-Blue NF-κB Cells 4 suppliers Inquiry

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