MALT1 Inhibitors and Degraders: Strategies for NF-κB-Driven Malignancies

Mucosa-associated lymphoid tissue protein 1 (MALT1), a cysteine protease and the sole paracaspase in humans, plays a pivotal role in the survival and proliferation of NF-κB-dependent malignant cancers, particularly MALT lymphoma and diffuse large B-cell lymphoma (DLBCL). Dysregulated MALT1 activity is implicated in various malignancies, highlighting its importance as a therapeutic target. This Perspective provides an overview of MALT1's structural and functional characteristics, summarizes recent advancements in small-molecule inhibitors and degraders targeting this protein, and discusses compound structures, structure-activity relationship (SAR) analyses, and biological activities. We aim to inform future research efforts to enhance the activity, selectivity, and pharmacological properties of MALT1-targeting compounds, establishing a foundational framework for drug development in this critical area of cancer therapy.