MALT1 Small Molecule Inhibitors Specifically Suppress ABC-DLBCL In Vitro and In Vivo

被引：219

作者：

Fontan, Lorena ^{[2
,3
,5
]}

Yang, Chenghua ^{[1
]}

Kabaleeswaran, Venkataraman ^{[1
,6
,7
]}

Volpon, Laurent ^{[8
]}

Osborne, Michael J. ^{[8
]}

Beltran, Elena ^{[5
]}

Garcia, Monica ^{[2
,3
]}

Cerchietti, Leandro ^{[2
]}

Shaknovich, Rita ^{[2
,4
]}

Yang, Shao Ning ^{[2
]}

Fang, Fang ^{[2
,3
]}

Gascoyne, Randy D. ^{[9
]}

Angel Martinez-Climent, Jose ^{[5
]}

Glickman, J. Fraser ^{[10
]}

Borden, Katherine ^{[8
]}

Wu, Hao ^{[1
,6
,7
]}

Melnick, Ari ^{[2
,3
]}

机构：

[1] Weill Cornell Med Coll, Dept Biochem, New York, NY 10021 USA

[2] Weill Cornell Med Coll, Div Hematol & Med Oncol, New York, NY 10021 USA

[3] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA

[4] Weill Cornell Med Coll, Dept Pathol, Div Immunopathol, New York, NY 10021 USA

[5] Univ Navarra, Ctr Appl Med Res, Div Oncol, Navarra 31008, Spain

[6] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[8] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada

[9] BC Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 1L3, Canada

[10] Rockefeller Univ, High Throughput Screening Resource Ctr, New York, NY 10065 USA

来源：

CANCER CELL | 2012年 / 22卷 / 06期

关键词：

B-CELL LYMPHOMA; NF-KAPPA-B; KINASE-C INHIBITOR; T-CELL; CHROMOSOMAL TRANSLOCATION; PARACASPASE MALT1; CRYSTAL-STRUCTURE; PROTEASE ACTIVITY; HODGKIN-LYMPHOMA; TISSUE LYMPHOMA;

D O I：

10.1016/j.ccr.2012.11.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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

引用

页码：812 / 824

页数：13

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