title: MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo.
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.
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: Fontan
authors.forename: Chenghua
authors.initials: C
authors.lastname: Yang
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Kabaleeswaran
authors.forename: Laurent
authors.initials: L
authors.lastname: Volpon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Osborne
authors.forename: Elena
authors.initials: E
authors.lastname: Beltran
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Jose Angel
authors.initials: JA
authors.lastname: Martinez-Climent
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Glickman
authors.forename: Katherine
authors.initials: K
authors.lastname: Borden
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D059748:Proteolysis; D020569:Proto-Oncogene Proteins c-rel; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011480:Protease Inhibitors; D020569:Proto-Oncogene Proteins c-rel; C068059:REL protein, human; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein