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.
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.
