Deciphering the Role and Potential of Paracaspase MALT1 Inhibitors in Hematological Cancers

MALT1 is a crucial protein in the NF-κB signaling pathway and is associated with a subset of B-cell lymphomas, making it a potential therapeutic target for these cancers. A new class of MALT1 inhibitors has been discovered that show promise in inhibiting the proliferation of non-Hodgkin B-cell lymphoma cells.

Utilizing a sophisticated Free Energy Perturbation (FEP+) modeling technology, researchers have identified small molecule inhibitors that potently suppress MALT1 enzymatic activity and exhibit high binding affinity to the MALT1 protein. These inhibitors have been shown to prevent the cleavage of BCL10, a protein targeted by MALT1, in specific diffuse large B cell lymphoma (DLBCL) cell lines that are either resistant or responsive to Bruton tyrosine kinase (BTK) inhibitor ibrutinib.

The study found that these compounds are highly effective at inhibiting IL10 secretion, which is indicative of NF-κB signaling inhibition. Moreover, the MALT1 inhibitors have demonstrated significant anti-proliferative effects on DLBCL cell lines and have shown synergistic effects when combined with ibrutinib.

In addition to their efficacy in vitro, these inhibitors have also displayed excellent selectivity and a significant safety margin in a high dose tolerability study. Plasma IL10 and tumor BCL10 have been identified as potential pharmacodynamic markers in preclinical studies involving mice with DLBCL tumors. Tumor growth inhibition was observed following treatment with the inhibitors, and the combination with venetoclax showed enhanced efficacy.

Ongoing research is focused on exploring the synergistic effects of these compounds with BTK inhibitors in mouse models of B-cell lymphoma. Initial results indicate that the inhibitors can potently suppress IL-2 secretion in Jurkat cells, and further studies are being conducted to understand the role of MALT1 inhibition in T regulatory and effector T cells.

The refinement of the current series of inhibitors, informed by co-crystal structures, is underway to develop optimized molecules for future clinical applications. The discovery of these potent MALT1 protease inhibitors presents a potential advancement in the treatment of B-cell lymphomas, particularly for patients with ABC-DLBCL, and may offer new therapeutic options for those with relapsed or refractory disease.