MALT1 cleavage activity is linked to the pathogenesis of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), a chemo-resistant 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 suppression of NF-ĸB reporter activity, inhibition of nuclear localization of c-REL and downregulation of NF-ĸB target gene signature. Most notably, MI-2 was non-toxic to mice, and displayed potent and specific activity against ABC-DLBCL cell lines
