MALT1 Small Molecule Inhibitors Specifically Suppress ABC-DLBCL In Vitro and In Vivo
Menées in vitro et in vivo, ces deux études mettent en évidence l'intérêt de cibler la paracaspase MALT1 pour le traitement d'une forme chimiorésistante du lymphome diffus à grandes cellules B
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-
κ
B reporter activity suppression, c-REL nuclear localization inhibition, and NF-
κ
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.
º Development of a method for generating active MALT1 paracaspase in vitro
º Identification of MI-2, an irreversible MALT1 inhibitor with nanomolar activity
º MI-2 is nontoxic and effective in suppressing NF-
κ
B signaling and ABC-DLBCL in vivo
º MI-2 suppresses primary human DLBCL cells; hence, MALT1 is a viable therapeutic target
Cancer cell , résumé, 2011