Natural Product Inhibitors of the Arginine-Specific Protease Activity of MALT1

MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a multi-domain protein that plays a critical role in NF-κB activation. It has been implicated in lymphomas, multiple myeloma, and epithelial cancers, and it plays a key role in regulating the immune response to infection. MALT1 possesses a proteolytic paracaspase domain that cleaves arginine-containing substrates, and inhibition of this protease activity by RNAi has been shown to reduce survival of various lymphoma cell lines. Thus, molecularly-targeted strategies directed towards MALT1 protease activity have significant therapeutic potential. An enzymatic high-throughput assay that employed full-length human MALT1 and a fluorescently labeled peptide substrate (acetyl-Leu-Arg-Ser-Arg-4-methyl-coumaryl-7-amide) was developed and used to screen extracts from the NCI Natural Products Repository. A number of extracts were active in this screen and they were subjected to detailed chemical study. Bioassay-guided fraction of these extracts and the resulting MALT1 inhibitory natural products will be described.