title: Development of new Malt1 inhibitors and probes.
abstract: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) is a promising therapeutic target for the treatment of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Several research groups have reported on the development of Malt1 inhibitors and activity-based probes for in vitro and in situ monitoring and modulating Malt1 activity. In this paper, we report on two activity-based Malt1 probes (6 and 7) and a focused library of 19 new Malt1 inhibitors. Our peptide-based probe 6 labels Malt1 in an activity-based manner. In contrast, probe 7, derived from the known covalent inhibitor MI-2, labels both wild type and catalytically inactive Cys to Ala mutant Malt1, suggesting that MI-2 inhibits Malt1 by reacting with a nucleophilic residue other than the active site cysteine. Furthermore, two of our inhibitors (9, apparent IC50 3.0μM, and 13, apparent IC50 2.1μM) show good inhibitory activity against Malt1 and outperform MI-2 (apparent IC50 7.8μM) in our competitive activity-based protein profiling assay.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
authors.forename: Bo-Tao
authors.initials: BT
authors.lastname: Xin
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Gisela
authors.initials: G
authors.lastname: Schimmack
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Du
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Florea
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.affiliation: Kantonsspital St. Gallen, Rorschacher Strasse 95, St. Gallen, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Driessen
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstaedter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands. Electronic address: h.s.overkleeft@chem.leidenuniv.nl.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
mesh_terms: D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D061945:Caspase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002219:Carbamates; D061945:Caspase Inhibitors; D009363:Neoplasm Proteins; D014230:Triazoles; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
keywords: Activity-based protein profiling; Lymphoma; Malt1; Malt1 inhibitors; Mechanism-based inhibitor