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Open Access Green as soon as Postprint is submitted to ZB.
Development of new Malt1 inhibitors and probes.
Bioorg. Med. Chem. 24, 3312-3329 (2016)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Activity-based Protein Profiling ; Lymphoma ; Malt1 ; Malt1 Inhibitors ; Mechanism-based Inhibitor; T-cell-activation; Paracaspase Malt1; Abc-dlbcl; Lymphoma; Metacaspases; Cleavage; Protease; Key
ISSN (print) / ISBN
0968-0896
e-ISSN
1464-3391
Quellenangaben
Volume: 24,
Issue: 15,
Pages: 3312-3329
Publisher
Elsevier
Publishing Place
Oxford
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Signaling and Translation (SAT)