Structure?Activity Relationship Studies Of 3-Substituted Pyrazoles As Novel Allosteric Inhibitors Of Malt1 Protease

We report the discovery of a novel series of 1,5-bisphenylpyrazoles as potent MALT1 inhibitors. Structure?activity relationship exploration of a hit compound led to a potent MALT1 inhibitor. Compound 33 showed strong activity against MALT1 (IC50: 0.49 ?M), potent cellular activity (NF-?B inhibition and inhibition of IL2 production), and high selectivity against caspase-3, -8, and -9. The results of a kinetics study suggest that compound 33 is a non-competitive inhibitor of MALT1 protein.