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

被引：220

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

共 47 条

[1] Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling [J].

Alizadeh, AA ;

Eisen, MB ;

Davis, RE ;

Ma, C ;

Lossos, IS ;

Rosenwald, A ;

Boldrick, JG ;

Sabet, H ;

Tran, T ;

Yu, X ;

Powell, JI ;

Yang, LM ;

Marti, GE ;

Moore, T ;

Hudson, J ;

Lu, LS ;

Lewis, DB ;

Tibshirani, R ;

Sherlock, G ;

Chan, WC ;

Greiner, TC ;

Weisenburger, DD ;

Armitage, JO ;

Warnke, R ;

Levy, R ;

Wilson, W ;

Grever, MR ;

Byrd, JC ;

Botstein, D ;

Brown, PO ;

Staudt, LM .

NATURE, 2000, 403 (6769) :503-511

[2] A unified model for apical caspase activation [J].

Boatright, KM ;

Renatus, M ;

Scott, FL ;

Sperandio, S ;

Shin, H ;

Pedersen, IM ;

Ricci, JE ;

Edris, WA ;

Sutherlin, DP ;

Green, DR ;

Salvesen, GS .

MOLECULAR CELL, 2003, 11 (02) :529-541

[3] BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy [J].

Cerchietti, Leandro C. ;

Hatzi, Katerina ;

Caldas-Lopes, Eloisi ;

Yang, Shao Ning ;

Figueroa, Maria E. ;

Morin, Ryan D. ;

Hirst, Martin ;

Mendez, Lourdes ;

Shaknovich, Rita ;

Cole, Philip A. ;

Bhalla, Kapil ;

Gascoyne, Randy D. ;

Marra, Marco ;

Chiosis, Gabriela ;

Melnick, Ari .

JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (12) :4569-4582

[4] Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma [J].

Compagno, Mara ;

Lim, Wei Keat ;

Grunn, Adina ;

Nandula, Subhadra V. ;

Brahmachary, Manisha ;

Shen, Qiong ;

Bertoni, Francesco ;

Ponzoni, Maurilio ;

Scandurra, Marta ;

Califano, Andrea ;

Bhagat, Govind ;

Chadburn, Amy ;

Dalla-Favera, Riccardo ;

Pasqualucci, Laura .

NATURE, 2009, 459 (7247) :717-U124

[5] T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20 [J].

Coornaert, Beatrice ;

Baens, Mathijs ;

Heyninck, Karen ;

Bekaert, Tine ;

Haegman, Mira ;

Staal, Jens ;

Sun, Lijun ;

Chen, Zhijian J. ;

Marynen, Peter ;

Beyaert, Rudi .

NATURE IMMUNOLOGY, 2008, 9 (03) :263-271

[6] Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma [J].

Davis, R. Eric ;

Ngo, Vu N. ;

Lenz, Georg ;

Tolar, Pavel ;

Young, Ryan M. ;

Romesser, Paul B. ;

Kohlhammer, Holger ;

Lamy, Laurence ;

Zhao, Hong ;

Yang, Yandan ;

Xu, Weihong ;

Shaffer, Arthur L. ;

Wright, George ;

Xiao, Wenming ;

Powell, John ;

Jiang, Jian-Kang ;

Thomas, Craig J. ;

Rosenwald, Andreas ;

Ott, German ;

Muller-Hermelink, Hans Konrad ;

Gascoyne, Randy D. ;

Connors, Joseph M. ;

Johnson, Nathalie A. ;

Rimsza, Lisa M. ;

Campo, Elias ;

Jaffe, Elaine S. ;

Wilson, Wyndham H. ;

Delabie, Jan ;

Smeland, Erlend B. ;

Fisher, Richard I. ;

Braziel, Rita M. ;

Tubbs, Raymond R. ;

Cook, J. R. ;

Weisenburger, Dennis D. ;

Chan, Wing C. ;

Pierce, Susan K. ;

Staudt, Louis M. .

NATURE, 2010, 463 (7277) :88-U97

[7] Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma [J].

Farinha, P ;

Gascoyne, RD .

JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (26) :6370-6378

[8] MALT1 directs B cell receptor-induced canonical nuclear factor-κB signaling selectively to the c-Rel subunit [J].

Ferch, Uta ;

zum Bueschenfelde, Christian Meyer ;

Gewies, Andreas ;

Wegener, Elmar ;

Rauser, Sandra ;

Peschel, Christian ;

Krappmann, Daniel ;

Ruland, Juergen .

NATURE IMMUNOLOGY, 2007, 8 (09) :984-991

[9] Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells [J].

Ferch, Uta ;

Kloo, Bernhard ;

Gewies, Andreas ;

Pfaender, Vera ;

Duewel, Michael ;

Peschel, Christian ;

Krappmann, Daniel ;

Ruland, Juergen .

JOURNAL OF EXPERIMENTAL MEDICINE, 2009, 206 (11) :2313-2320

[10] Proteasome Inhibitors: Recent Advances and New Perspectives In Medicinal Chemistry [J].

Genin, E. ;

Reboud-Ravaux, M. ;

Vidal, J. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2010, 10 (03) :232-256

← 1 2 3 4 5 →