期刊
CANCER CELL
卷 22, 期 6, 页码 812-824出版社
CELL PRESS
DOI: 10.1016/j.ccr.2012.11.003
关键词
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资金
- Spanish Ministry of Science Fellowship Sara Borrell
- Irvington Institute Postdoctoral Fellowship Program of the Cancer Research Institute
- Leukemia and Lymphoma Society Translational Research Program [6210-12]
- Chemotherapy Foundation
- Beverly and Raymond Sackler Center for Physical and Biomedical Sciences
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 NE-kappa B reporter activity suppression, c-REL nuclear localization inhibition, and NF-kappa B 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.
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