Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease

Abstract We describe a series of potent and highly selective small-molecule MALT1inhibitors, optimized from a High-Throughput Screeninghit. Advanced analogues such as compound 40 show high potency ( IC50: 0.01 µM) in a biochemical assay measuring MALT1enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.05 µM) and IL6/10 secretion ( IC50: 0.10/0.06 µM) in the TMD8 B-cell lymphomaline. Compound 40 also inhibited cleavage of the MALT1substrate RelB( IC50: 0.10 µM). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.