Publikation

Development of new Malt1 inhibitors and probes

Wissenschaftlicher Artikel/Review - 28.03.2016

Bereiche
PubMed
DOI

Zitation
Xin B, Schimmack G, Du Y, Florea B, van der Marel G, Driessen C, Krappmann D, Overkleeft H. Development of new Malt1 inhibitors and probes. Bioorg Med Chem 2016; 24:3312-29.
Art
Wissenschaftlicher Artikel/Review (Englisch)
Zeitschrift
Bioorg Med Chem 2016; 24
Veröffentlichungsdatum
28.03.2016
eISSN (Online)
1464-3391
Seiten
3312-29
Kurzbeschreibung/Zielsetzung

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.