| Title | MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. |
| Publication Type | Journal Article |
| Year of Publication | 2012 |
| Authors | Fontan L, Yang C, Kabaleeswaran V, Volpon L, Osborne MJ, Beltran E, Garcia M, Cerchietti L, Shaknovich R, Yang SNing, Fang F, Gascoyne RD, Martinez-Climent JAngel, J Glickman F, Borden K, Wu H, Melnick A |
| Journal | Cancer Cell |
| Volume | 22 |
| Issue | 6 |
| Pagination | 812-24 |
| Date Published | 2012 Dec 11 |
| ISSN | 1878-3686 |
| Keywords | Animals, 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, Neoplasm Proteins, NF-kappa B, Nuclear Proteins, Protease Inhibitors, Proteolysis, Xenograft Model Antitumor Assays |
| 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. |
| DOI | 10.1016/j.ccr.2012.11.003 |
| Alternate Journal | Cancer Cell |
| PubMed ID | 23238016 |
| PubMed Central ID | PMC3984478 |
| Grant List | R01 AI089882 / AI / NIAID NIH HHS / United States |