MALT1 (MALT1 Paracaspase)

This study explored the role of MALT1 in GBM's immunosuppressive microenvironment, developed a novel MALT1-related prognostic model, and identified potential targeted therapies for GBM, providing new avenues for therapeutic intervention.

Notably, agents such as safimaltib (JNJ-67856633) have shown manageable safety profiles and preliminary antitumor activity in early-phase trials for relapsed/refractory B-cell malignancies. However, MALT1-targeted therapy poses a dual challenge: although inhibiting oncogenic signaling and tumor cell proliferation, it also disrupts immunosuppressive Treg function, risking autoimmune toxicity by compromising the tumor microenvironment. This review systematically analyzes MALT1's oncogenic roles across cancers, clarifies inhibitor mechanisms, and evaluates translational challenges and strategic opportunities for precision oncology and combination immunotherapy.

Provided herein are novel compounds as MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

MALT1 inhibition, which impacts on NF-κB signaling, led to a robust effect in vitro that was partially reproduced in the NSG model. Our investigations revealed the actual possibility of inhibiting downstream TCR signaling by CARD11, BCL10 and MALT1 in SS therapy.

The effects of MALT1 knockdown and overexpression on Th1 and Th17 cell differentiation were hampered by PMA and BAY treatment, respectively. MALT1 knockdown alleviates LPS-induced multiorgan injury and inflammation probably through inhibiting the TAK1/NF-κB signaling pathway-mediated Th1 and Th17 differentiation.

Succinate triggers CCL2 release in macrophages via the GPR91/MALT1/NF-κB pathway, thereby exacerbating pulmonary fibrosis. These findings suggest that targeting succinate signaling may represent a novel therapeutic strategy for IPF.

Hence, the presented results can be used as an objective criterion for the computational proposal of new MALT1 allosteric inhibitors. However, despite mouse MALT1 and human MALT1 presenting 93% homology, the generalization of the findings to human MALT1 protein should be taken with care, and the obtained results apply specifically to the mouse MALT1 construct.

Co-administration with posaconazole increased SGR-1505 exposure 3-fold...Asymptomatic, reversible indirect hyperbilirubinemia occurred, consistent with inhibition of UGT1A1. SGR-1505 was well-tolerated and exhibited favorable pharmacokinetic and pharmacodynamic properties, supporting further clinical development.

P2, N=50, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Dec 2025 --> Dec 2027

Importantly, the combined MD-NMR analysis demonstrates that the NMR-initiated ensembles provide the most faithful representation of backbone and loop dynamics under low-salt conditions, capturing substrate-independent loop rearrangements, stable hydrophobic-core behaviour, and the intrinsic transitions that shape MALT1's conformational equilibrium. Together, these findings identify ionic strength as a key regulator of MALT1 conformational equilibria,, highlighting how loop dynamics and domain flexibility tune its proteolytic competence and providing a dynamic framework for future structure-based modulation of MALT1 activity.

As this study is purely computational, experimental validation is required to confirm these findings. The online version contains supplementary material available at 10.1007/s40203-025-00466-7.

This review provides an overview of the research progress and structure-activity relationships (SARs) of MALT1 inhibitors, including covalent inhibitors, allosteric inhibitors, PROTACs (Proteolysis-Targeting Chimeras), and activity-based probes. Additionally, it discusses the future opportunities and challenges in this field, aiming to provide insights for the future development of MALT1-targeted drugs.