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

  • Cancer Cell. 2012 Dec 11;22(6):812-24. doi: 10.1016/j.ccr.2012.11.003.
Lorena Fontan  1 ,  Chenghua Yang ,  Venkataraman Kabaleeswaran ,  Laurent Volpon ,  Michael J Osborne ,  Elena Beltran ,  Monica Garcia ,  Leandro Cerchietti ,  Rita Shaknovich ,  Shao Ning Yang ,  Fang Fang ,  Randy D Gascoyne ,  Jose Angel Martinez-Climent ,  J Fraser Glickman ,  Katherine Borden ,  Hao Wu ,  Ari Melnick
Affiliations
  • 1. Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY 10021, USA.
PMID: 23238016 DOI: 10.1016/j.ccr.2012.11.003
Abstract

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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