MALT1 PROTAC
Molecular Target
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease
E3 Ligase
Cereblon (CRBN)
Biological Role
MALT1 lies downstream of activating mutations in the BCR/NFkB signaling pathway that drives ABC-DLBCL proliferation. MALT1 protease cleaves and inactivates inhibitors of the NFkB signaling pathway such as A20 and RelB. MALT1 also functions as a scaffold with CARD11 and BCL10 to recruit and activate IKK towards IkBa. The PROTAC was developed as an in vitro tool to investigate MALT1 scaffold versus protease function.
Activity
>85% MALT1 degradation with the PROTAC 5 (0.1μM) and increased RelB expression correlated with the percentage of MALT1 degradation. However, only partial/no growth inhibition was observed with MALT1 PROTACs at 0.1-1μM concentrations and similar phenotypes for ABC-DLBCL cell growth inhibition were observed between PROTACs, small molecules, and CRISPR cell lines.