[PDF][PDF] MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo

L Fontan, C Yang, V Kabaleeswaran, L Volpon… - Cancer cell, 2012 - cell.com
L Fontan, C Yang, V Kabaleeswaran, L Volpon, MJ Osborne, E Beltran, M Garcia…
Cancer cell, 2012cell.com
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 …
Summary
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.
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