MALT1 Small Molecule Inhibitors Specifically Suppress ABC-DLBCL In Vitro and In Vivo

Abstract

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.

TWIST1 is a molecular marker for a poor prognosis in oral cancer and represents a potential therapeutic target

“…35,36 However, recent advances in the design of small molecules and peptides and of nanotechnologies for drug-delivery approaches are opening new avenues in drug discovery to target transcription factors like Twist1. 37 In summary, this study provides insights into the relevance of Twist1 and regulated genes for the progression of poorly differentiated OSCC to metastasis and highlights their potential to be exploited as therapeutic targets for advanced OSCC.…”

The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling

“…The resulting aberrant activation of NF-κB and of MALT1 counteracts cell death and promotes unlimited growth (Shaffer et al, 2012). In return, ABC DLBCL cells develope a profound addiction to the CBM-NF-κB nexus and to MALT1 catalytic activity (Ferch et al, 2009;Fontan et al, 2012;Hailfinger et al, 2009;Nagel et al, 2012;Ngo et al, 2006).…”

Germinating MALT1

“…His team showed that the antipsychotic compounds mepazine and thioridazine were also nanomolar-potent MALT1 inhibitors with in vivo efficacy in ABC-DLBCL. 8 Krappmann told SciBX that his team has since synthesized new inhibitors but also sees potential for thioridazine in the clinic. "We are in the process of working out a clinical repurposing trial with thioridazine because this drug is still available.…”