TitlePeptide-based covalent inhibitors of MALT1 paracaspase.
Publication TypeJournal Article
Year of Publication2019
AuthorsHatcher, John M., Du Guangyan, Fontan Lorena, Us Ilkay, Qiao Qi, Chennamadhavuni Spandan, Shao Jay, Wu Hao, Melnick Ari, Gray Nathanael S., and Scott David A.
JournalBioorg Med Chem Lett
Date Published2019 Jun 01
KeywordsCaspase Inhibitors, Dose-Response Relationship, Drug, Humans, Molecular Structure, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Peptides, Structure-Activity Relationship

<p>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.</p>

Alternate JournalBioorg Med Chem Lett
PubMed ID30954428
Grant ListR01 AI050872 / AI / NIAID NIH HHS / United States
R01 CA182736 / CA / NCI NIH HHS / United States