Author/Authors :
Nagel، نويسنده , , Daniel and Spranger، نويسنده , , Stefani and Vincendeau، نويسنده , , Michelle and Grau، نويسنده , , Michael and Raffegerst، نويسنده , , Silke and Kloo، نويسنده , , Bernhard and Hlahla، نويسنده , , Daniela and Neuenschwander، نويسنده , , Martin and Peter von Kries، نويسنده , , Jens and Hadian، نويسنده , , Kamyar and Dِrken، نويسنده , , Bernd and Lenz، نويسنده , , Peter and Lenz، نويسنده , , Georg and Schendel، نويسنده , , Dolores J. and Krappmann، نويسنده , , Daniel، نويسنده ,
Abstract :
Summary
lytic activity of the mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) paracaspase is required for survival of the activated B cell subtype of diffuse large B cell lymphoma (ABC-DLBCL). We have identified distinct derivatives of medicinal active phenothiazines, namely mepazine, thioridazine, and promazine, as small molecule inhibitors of the MALT1 protease. These phenothiazines selectively inhibit cleavage activity of recombinant and cellular MALT1 by a noncompetitive mechanism. Consequently, the compounds inhibit anti-apoptotic NF-κB signaling and elicit toxic effects selectively on MALT1-dependent ABC-DLBCL cells in vitro and in vivo. Our data provide a conceptual proof for a clinical application of distinct phenothiazines in the treatment of ABC-DLBCL.
