TitleMALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo.
Publication TypeJournal Article
Year of Publication2012
AuthorsFontan, Lorena, Yang Chenghua, Kabaleeswaran Venkataraman, Volpon Laurent, Osborne Michael J., Beltran Elena, Garcia Monica, Cerchietti Leandro, Shaknovich Rita, Yang Shao Ning, Fang Fang, Gascoyne Randy D., Martínez-Climent Jose Angel, J Glickman Fraser, Borden Katherine, Wu Hao, and Melnick Ari
JournalCancer Cell
Date Published2012 Dec 11
KeywordsAnimals, B-Lymphocytes, Caspases, Catalysis, Cell Line, Tumor, Cell Proliferation, DNA-Binding Proteins, Down-Regulation, Humans, Lymphoma, Large B-Cell, Diffuse, Male, Mice, Mice, Inbred NOD, Mice, SCID, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Neoplasm Proteins, NF-kappa B, Nuclear Proteins, Protease Inhibitors, Proteolysis, Proto-Oncogene Proteins c-rel, Xenograft Model Antitumor Assays

<p>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.</p>

Alternate JournalCancer Cell
PubMed ID23238016
PubMed Central IDPMC3984478
Grant ListR01 AI089882 / AI / NIAID NIH HHS / United States