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 MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC50 0.01 µM) in a biochemical assay measuring MALT1 enzymatic 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 lymphoma line. Compound 40 also inhibited cleavage of the MALT1 substrate RelB (IC50 0.10 µM). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.