Abstract
MALT1 cleavage activity is linked to the pathogenesis of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), a chemoresistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors. A selected lead compound, MI-2, featured direct binding to MALT1 and suppression of its protease function. MI-2 concentrated within human ABC-DLBCL cells and irreversibly inhibited cleavage of MALT1 substrates. This was accompanied by NF-κB reporter activity suppression, c-REL nuclear localization inhibition, and NF-κB target gene downregulation. Most notably, MI-2 was nontoxic to mice, and displayed selective activity against ABC-DLBCL cell lines in vitro and xenotransplanted ABC-DLBCL tumors in vivo. The compound was also effective against primary human non-germinal center B cell-like DLBCLs ex vivo.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / drug effects*
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B-Lymphocytes / metabolism
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Caspases / metabolism
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Catalysis
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Down-Regulation / drug effects
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Humans
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Lymphoma, Large B-Cell, Diffuse / drug therapy*
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Lymphoma, Large B-Cell, Diffuse / pathology
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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NF-kappa B / metabolism
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / metabolism
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Protease Inhibitors / pharmacology*
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Proteolysis
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Proto-Oncogene Proteins c-rel
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Xenograft Model Antitumor Assays
Substances
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DNA-Binding Proteins
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NF-kappa B
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Neoplasm Proteins
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Nuclear Proteins
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Protease Inhibitors
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Proto-Oncogene Proteins c-rel
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REL protein, human
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Caspases
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MALT1 protein, human
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein