MALT1 as a promising target to treat lymphoma and other diseases related to MALT1 anomalies

Abstract

Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key adaptor protein that regulates the NF‐κB pathway, in which MALT1 functions as a scaffold protein and protease to trigger downstream signals. The abnormal expression of MALT1 is closely associated with lymphomagenesis and other diseases, including solid tumors and autoimmune diseases. MALT1 is the only protease in the underlying pathogenesis of these diseases, and its proteolytic activity can be pharmacologically regulated. Therefore, MALT1 is a potential and promising target for anti‐lymphoma and other MALT1‐related disease treatments. Currently, the development of MALT1 inhibitors is still in its early stages. This review presents an overview of MALT1, particularly its X‐ray structures and biological functions, and elaborates on the pathogenesis of diseases associated with its dysregulation. We then summarize previously reported MALT1 inhibitors, focusing on their molecular structure, biological activity, structure–activity relationship, and limitations. Finally, we propose future research directions to accelerate the discovery of novel MALT1 inhibitors with clinical applications. Overall, this review provides a comprehensive and systematic overview of MALT1‐related research advances and serves as a theoretical basis for drug discovery and research.

Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma

“…We then evaluated the in vitro MALT1 inhibition effect for all synthesized derivatives. Thioridazine, a reported noncovalent selective MALT1 inhibitor, was used as the positive control. ,, As summarized in Table , we first investigated the inhibition effect of the structure skeleton with different substituents on MALT1 protease activity. Compound 14a , the structure skeleton with a hydrogen atom substituent, showed a weak in vitro MALT1 inhibition with the IC 50 value over 25 μM.…”

“…However, there have been few research and development cases of MALT1 inhibitors so far. 31 Therefore, the development of MALT1 inhibitors is urgent for the treatment of lymphoma. Herein, we identified and designed a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo-[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives and demonstrated their excellent antitumor effects on ABC-DLBCL cells.…”

“…MALT1 inhibitors could be a promising and powerful approach for activated B cell-like diffuse large B cell lymphoma treatment. However, there have been few research and development cases of MALT1 inhibitors so far . Therefore, the development of MALT1 inhibitors is urgent for the treatment of lymphoma.…”

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

“…Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a unique paracaspase and key component of the CARD11/MALT1/BCL10 complex that mediates NF-κB signalling [ 120 , 121 ]. When dysregulated, MALT1 acts as a proto-oncogene and is known to contribute to tumorigenesis in lymphoid malignancies, including a prominent role in MALT lymphoma and activated B-cell type DLBCL [ 122 ].…”

“…Three main classes of MALT1 inhibitors are in development: allosteric, covalent and protein degraders [ 121 , 123 ]. Pre-clinical studies have demonstrated in vivo and in vitro suppression of the growth of the ABC-DLBCL cell [ 123 , 124 , 125 ].…”