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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-?B reporter activity suppression, c-REL nuclear localization inhibition, and NF-?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.

SUBMITTER: Fontan L

PROVIDER: S-EPMC3984478 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Fontan Lorena L Yang Chenghua C Kabaleeswaran Venkataraman V Volpon Laurent L Osborne Michael J MJ Beltran Elena E Garcia Monica M Cerchietti Leandro L Shaknovich Rita R Yang Shao Ning SN Fang Fang F Gascoyne Randy D RD Martinez-Climent Jose Angel JA Glickman J Fraser JF Borden Katherine K Wu Hao H Melnick Ari A

Cancer cell 20121201 6

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 ...[more]

PMID: 23238016

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

Publications

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

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