Author/Authors :
Fontan، نويسنده , , Lorena and Yang، نويسنده , , Chenghua and Kabaleeswaran، نويسنده , , Venkataraman and Volpon، نويسنده , , Laurent and Osborne، نويسنده , , Michael J. and Beltran، نويسنده , , Elena Zaballos-Garcia، نويسنده , , Monica and Cerchietti، نويسنده , , Leandro and Shaknovich، نويسنده , , Rita and Yang، نويسنده , , Shao Ning and Fang، نويسنده , , Fang and Gascoyne، نويسنده , , Randy D. and Martinez-Climent، نويسنده , , Jose Angel and Glickman، نويسنده , , J. Fraser and Borden، نويسنده , , Katherine C. Wu، نويسنده , , Hao and Melnick، نويسنده , , Ari، نويسنده ,
Abstract :
Summary
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.
