Peptide-based covalent inhibitors of MALT1 paracaspase. Issue 11 (1st June 2019)

• Record Type: Journal Article
• Authors: Hatcher, John M.; Du, Guangyan; Fontán, Lorena; Us, Ilkay; Qiao, Qi; Chennamadhavuni, Spandan; Shao, Jay; Wu, Hao; Melnick, Ari; Gray, Nathanael S.; Scott, David A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 11(2019)
• Page Start: 1336
• Page End: 1339
• Publication Date: 2019-06-01
• Subjects: Inhibitors -- Protease -- Covalent -- Peptide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.03.046
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Potent and selective substrate-based covalent inhibitors of MALT1 protease were developed from the tetrapeptide tool compound Z-VRPR-fmk. To improve cell permeability, we replaced one arginine residue. We further optimized a series of tripeptides and identified compounds that were potent in both a GloSensor reporter assay measuring cellular MALT1 protease activity, and an OCI-Ly3 cell proliferation assay. Example compounds showed good overall selectivity towards cysteine proteases, and one compound was selected for further profiling in ABL-DLBCL cells and xenograft efficacy models.