A cell-permeable chloromethyl amide that inhibits MALT1 proteolytic activity (IC50 = 5.84uM against MALT1 paracaspase domain dimer-catalyzed Ac-LRSR-AMC hydrolysis) in an irreversible manner via covalent interaction, displaying little or no activity against caspase-3, -8, or -9. Due to irreversible binding and effective intracellular accumulation (HBL-1 intracellular [MI-2]t = 2h = 5uM; Medium [MI-2]t = 0 = 0.2uM), MI-2 is at least 250-times more effective than Z-VRPR-FMK in blocking constitutive NF-kappaB activity and c-Rel nuclear translocation in HBL-1 cultures (equal or better blockage by 200nM MI-2 than by 50uM Z-VRPR-FMK). Shown to selectively inhibit MALT1-dependent ABC-DLBCL proliferation, but not the MALT1-independent growths of ABC- (HLY-1 and U2932) or GCB-DLBCL (OCI-Ly1 and OCI-Ly7) cells, both in cultures in vitro (GI50 in 48h = 200, 400, 400, and 500nM, respectively, against HBL-1, OCI-Ly3, OCI-Ly10, and TMD8) and in mice in vivo (65%,, 61%, and 0% suppression, respectively, of HBL-1, TMD8, and OCI-Ly1 tumor expansion 24h after 14 daily 25mg/kg/day i.p. dosages) without any apparent toxicity to mice.
Solubility:DMSO
Primary Target:MALT1
Storage and Stability:Lyophilized powder may be stored at -20°C. Stable for 12 months after receipt at -20°C. Reconstitute with sterile buffer or ddH2O. Aliquot to avoid repeated freezing and thawing. Store at -20°C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Further dilutions can be made in assay buffer.
