MALT1 Is a Therapeutic Target in ABC–DLBCL

Patients with activated B cell–like diffuse large B-cell lymphoma (ABC-DLBCL) have the worst prognosis among those with DLBCL. Constitutive activation of NF-κB signaling is a hallmark of ABC–DLBCL and can occur as a result of activating mutations affecting B-cell receptor (BCR) subunits or the CARD11–BCL10–MALT1 (CBM) complex upstream of the canonical NF-κB pathway. Given that MALT1 paracaspase activity results in the cleavage and inactivation of negative regulators of NF-κB and is required in ABC–DLBCL cell lines, inhibition of MALT1 may be an effective therapeutic strategy in this aggressive disease. Potent small-molecule MALT1 inhibitors were identified in 2 independent high-throughput compound library screens that used an in vitro MALT1 protease assay in which a substrate emits fluorescence after cleavage. Fontan and colleagues identified a lead compound, MI-2, that covalently and irreversibly bound the active site of MALT1 to inhibit its protease activity, whereas Nagel and colleagues found that the phenothiazine derivatives mepazine, thioridazine, and promazine were noncompetitive, reversible MALT1 inhibitors. These compounds specifically inhibited cleavage of MALT1 targets and induced apoptosis in a dose-dependent manner in ABC–DLBCL cells but not in other DLBCL subtypes, culminating in downregulation of NF-κB targets. MI-2, mepazine, and thioridazine significantly suppressed the growth of MALT1-dependent ABC–DLBCL xenografts in association with decreased NF-κB signaling and proliferation and increased apoptosis. Further testing of MI-2 in primary patient samples also showed a significant reduction in the viability of ABC–DLBCL cells. Encouragingly, MI-2 was nontoxic in mice, and mepazine, thioridazine, and promazine have all been used clinically as antipsychotic agents or sedatives, suggesting that MALT1 inhibition may be safe and feasible through further clinical development of MI-2 or off-label use of phenothiazine derivatives.

Fontan L, Yang C, Kabaleeswaran V, Volpon L, Osbourne MJ, Beltran E, et al. MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell 2012;22:812–24.

Nagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, et al. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell 2012;22:825–37.