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.

Keywords: Allosteric inhibitors; Autoimmune diseases; Discovery and optimization; MALT1; Paracaspase.