- |||||||||| Review, Journal: MALT1 Inhibitors and Degraders: Strategies for NF-?B-Driven Malignancies. (Pubmed Central) - Feb 25, 2025
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.
- |||||||||| ZE66-0205 / Eilean Therap
Development of ZE66-0205, a Novel MALT1 Degrader for Treatment of B-Cell Malignancies (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5202;
ZE66-0205 leads to on target degradation of CBM target proteins and represents a promising new treatment strategy for DLBCL and other B-cell malignancies. Future clinical development of ZE66-0205 is warranted and ongoing.
- |||||||||| Calquence (acalabrutinib) / AstraZeneca
Oncogenic CARD11 Mutations and Autonomous BCR Signaling Act As Functionally Equivalent Alternative Drivers in ABC-DLBCL (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_4964;
TMD8 cells express a BCR with intermediate-high autonomous signaling and are highly sensitive to the BTK inhibitor acalabrutinib (IC50 = 0.005 nM) by the MTS viability assay...In the presence of these mutations, a BCR without autonomous signaling activity fails to rescue knock-out of the autonomous BCR signaling activity, indicating insufficiency of tonic BCR signaling. The low prevalence of the CARD11 L251P mutation emphasizes the importance of antigen-independent autonomous BCR signaling as a frequent non-genetic immunological driver mechanism and the need for detailed dissection of the relative functional contribution of genetic and immunological drivers, including the zygosity of driver mutations, in order to develop optimal individualized targeted therapy for DLBCL patients.
- |||||||||| safimaltib (JNJ-6633) / J&J
A Highly Selective and Orally Bioavailable CK1? Molecular Glue Degrader Targets B-Cell Lymphoma Cells (Ballroom 20CD (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2045;
degrader that targets both the NF-?B and p53 pathways, in offering new treatment strategy for lymphoma, including those resistant to BTK inhibitors. The results from this study not only position INNO-220 as a promising anti-cancer agent for B-cell lymphomas but also suggest a potential strategy for patient stratification, a crucial aspect of personalized medicine.
- |||||||||| Imbruvica (ibrutinib) / AbbVie, J&J
Biological and Prognostic Subgroups of Plasmablastic Lymphoma Defined By EBV Status and MYC Rearrangement (Pacific Ballroom Salons 15-17 (Marriott Marquis San Diego Marina)) - Nov 6, 2024 - Abstract #ASH2024ASH_1948;
Consistent with the lack of reliance on these pathways, functional analyses in PBL-1 showed resistance to treatment to ibrutinib as well as PI3K- and MALT1-inhibitors...We show that PBL does not rely on B-cell receptor signaling, instead relying on potentially targetable vulnerabilities in JAK-STAT, NOTCH, and RAS-RAF signaling according to EBV positivity and MYC rearrangement status. Lastly, we provide insight into the TME of PBL and demonstrate a novel population of SPP1 and CD44 expressing malignant cells in EBV+ tumors.
- |||||||||| thioridazine / Generic mfg.
Journal: In silico study of some plant compounds as potential anticancer agents targeting MALT1 allosteric domain. (Pubmed Central) - Sep 25, 2024
Our findings from this computational study presents cyanidin (-8.822 kcal/mol) as better binder to the allosteric site of MALT1 based on the molecular docking and pharmacokinetic profiling than thioridazine...Hence, cyanidin is a potential allosteric inhibitor of MALT1. However, an urgent need for in vitro and in vivo validations is required to ascertain the efficacy of cyanidin in the fight against cancer and other MALT1-related diseases.
- |||||||||| Journal: MALT1 Inhibitors for Treating Cancer and Immunological Diseases. (Pubmed Central) - Sep 20, 2024
However, an urgent need for in vitro and in vivo validations is required to ascertain the efficacy of cyanidin in the fight against cancer and other MALT1-related diseases. Provided herein are novel MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer and immunological diseases and processes for preparing such compounds.
- |||||||||| Journal, IO biomarker: Mucosa?associated lymphoid tissue lymphoma translocation protein 1 inhibitor, MI?2, attenuates non?small cell lung cancer cell proliferation, migration and invasion, and promotes apoptosis by suppressing the JNK/c?JUN pathway. (Pubmed Central) - Aug 9, 2024
However, NSCLC cell co-treatment with anisomycin (JNK pathway activator) reversed the effect of MI-2 on the proliferation, apoptosis and activation of the JNK/c-JUN pathway in NCI-H1650 and A549 cells. In conclusion, the present study demonstrated that the MALT1 inhibitor, MI-2, could suppress NSCLC cell proliferation, migration and invasion, and induce apoptosis via inactivating the JNK/c-JUN pathway.
- |||||||||| Journal: PRRSV utilizes MALT1-regulated autophagy flux to switch virus spread and reserve. (Pubmed Central) - Jul 31, 2024
In contrast, autophagosome accumulation upon MALT1 inhibition promoted PRRSV reserve for future virus proliferation once the autophagy flux recovers. Taken together, for the first time, these findings elucidate that MALT1 was utilized by PRRSV to regulate host autophagy flux, to determine the fate of virus for either proliferation or reserve.
- |||||||||| Journal, Immunogenic cell death, IO biomarker: Halting Multiple Myeloma with MALT1 Inhibition: Suppressing BCMA-Induced NF-?B and Inducing Immunogenic Cell Death. (Pubmed Central) - Jul 29, 2024
It was noteworthy that Mi-2 induces properties associated with immunogenic cell death (ICD), as evidenced by increased calreticulin (CRT), ATP release, and high-mobility group protein B1 (HMGB1) upregulation, consequently triggering ICD-associated immune activation and enhancing CD8+ T - cell cytotoxicity in vitro. In conclusion, our research highlights MALT1 as a promising druggable target for therapeutic interventions in MM, providing insights into its molecular mechanisms in MM progression.
- |||||||||| Journal: Inhibition of the MALT1-LPCAT3 axis protects cartilage degeneration and osteoarthritis. (Pubmed Central) - Mar 27, 2024
Overall, our data reveal a previously unrecognized role of the MALT1-LPCAT3 axis in osteoarthritis. Targeting the MALT1-LPCAT3 pathway with MALT1 inhibitors or siRNA-liposomes of LPCAT3 may become an effective strategy to treat OA by suppressing eicosanoids, matrix-degrading enzymes, and proinflammatory cytokines.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Journal, IO biomarker: Inhibition of MALT1 and BCL2 induces synergistic anti-tumor activity in models of B cell lymphoma. (Pubmed Central) - Mar 20, 2024
We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.
- |||||||||| Journal: MALT1 inhibition suppresses antigen-specific T cell responses. (Pubmed Central) - Mar 18, 2024
Thus, selective targeting of Tregs would be required to improve the immunotherapeutic effect of MALT1-inhibition. Also, various dosing schedules and combination therapy strategies should be carefully designed and evaluated further.
- |||||||||| sirolimus / Generic mfg.
Journal: MALT1 Protease Regulates T-Cell Immunity via the mTOR Pathway in Oral Lichen Planus. (Pubmed Central) - Jan 2, 2024
The effects of MALT1 and mechanistic target of rapamycin (mTOR) on T-cell immunity were investigated through western blot, CCK8 assay, and flow cytometry...MALT1 expression is aberrant in both local lesions and peripheral blood of OLP. Inhibition of the mTOR pathway further enhances the suppression of T-cell proliferation and the promotion of apoptosis induced by the MALT1 inhibitor MI-2.
- |||||||||| deferoxamine / Generic mfg.
Journal: Pharmacological inhibition of MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) induces ferroptosis in vascular smooth muscle cells. (Pubmed Central) - Dec 14, 2023
MI-2 treatment led to concentration- and time-dependent cell death of cultured aortic SMCs, which was rescued by the iron chelator deferoxamine (DFO) or ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, but not by inhibitors of apoptosis (Z-VAD-fmk), pyroptosis (Z-YVAD-fmk), or necrosis (Necrostatin-1, Nec-1)...Moreover, local application of MI-2 significantly reduced carotid neointima lesions and atherosclerosis in C57BL/6J mice and apolipoprotein-E knockout (ApoE) mice, respectively, which were both ameliorated by co-treatment with Fer-1. In conclusion, the present study demonstrated that MALT1 inhibition induces ferroptosis of vascular SMCs, likely contributing to its amelioration of proliferative vascular diseases.
- |||||||||| SGR-1505 / Schrodinger
A Phase 1, Open-Label, Multicenter, Dose-Escalation Study of Sgr-1505 As Monotherapy in Subjects with Mature B-Cell Malignancies (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_4032;
P1
Furthermore, a MALT1 inhibitor (JNJ-67856633) showed efficacy in mature B cell malignancies from phase 1 studies (ref 1, 2)...SGR-1505 administered as a single agent and in combination with the approved Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, demonstrates tumorostatic and regressive antitumor activity in ABC-DLBCL cell line-derived and patient-derived xenograft models...Subjects with symptomatic or active CNS involvement, and other conditions or laboratory findings placing them at increased risk to the use of an investigational drug are excluded. SGR-1505 is initially dose-escalated using an accelerated titration design in cohorts of 1-6 subjects, and at higher dose levels using a conventional 3+3 design.
- |||||||||| ABBV-525 / AbbVie
A First-in-Human Phase 1 Study of ABBV-525, a Small-Molecule MALT1 Inhibitor, in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_4031;
P1
Pts are being enrolled in 25 sites across the USA, Australia, Belgium, France, Germany, Israel, Spain, and UK. As of August 1, 2023, 2 pts had been treated.
- |||||||||| SGR-1505 / Schrodinger
Sgr-1505 Is a Potent MALT1 Protease Inhibitor with a Potential Best-in-Class Profile (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_3953;
P1
Changes in biological pathways mediated by MALT1 were also observed at relevant doses in the ongoing SGR-1505 healthy volunteer study. Currently, a phase 1 clinical trial in patients with mature B cell neoplasms is also ongoing (NCT05544019).
- |||||||||| GRK2, an Inhibitor of MALT1-Dependent Oncogenic Signaling, Is Downregulated By microRNA in ABC-DLBCL (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_1803;
Conclusions : Together, our data show that specific miRNAs (miR-148b, miR-125a and miR-125b) down-regulate GRK2 expression in ABC-DLBCL, which in turn enhances MALT1 scaffolding and proteolytic activities, leading to increased tumor cell proliferation. Future studies investigating miRNA inhibitors which enhance GRK2 expression and thereby suppress MALT1 activity may inform novel strategies for inhibiting MALT1-dependent lymphomagenesis.
- |||||||||| Incivek (telaprevir) / J&J, Vertex, Mitsubishi Tanabe
Preclinical, Journal: Telaprevir Improves Memory and Cognition in Mice Suffering Ischemic Stroke via Targeting MALT1-Mediated Calcium Overload and Necroptosis. (Pubmed Central) - Sep 7, 2023
According to these results, it can be concluded that telaprevir alleviates neuronal brain injury in stroke mice via restraining GluN2B activation and suppresses the receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway through inhibiting MALT1. Thus, telaprevir might have a novel indication for treating patients with ischemic stroke.
- |||||||||| Journal: Chemical Probes for Profiling of MALT1 Protease Activity. (Pubmed Central) - Aug 22, 2023
Such tools are valuable to validate MALT1 as a drug target in vivo and to assess yet unknown biological roles of MALT1. In this review we discuss the recent literature on the development and biological application of molecular tools to study MALT1 activity and inhibition.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute
Journal, IO biomarker: CARD11 gain of function upregulates BCL2A1 and promotes resistance to targeted therapies combination in B-cell lymphoma. (Pubmed Central) - Aug 10, 2023
Functional studies demonstrated that CARD11 gain of function not only resulted in BCR independence, but also directly increase the transcription of the antiapoptotic BCL2A1, leading to venetoclax and OAsIs combination resistance...Consequently, MALT1 inhibition induced synergistic cell death in combination with BCL2 inhibition, irrespective of CARD11 mutational status, both in vitro and in vivo. Taken together our study identified mechanisms of resistance to targeted therapies and provided a novel strategy to overcome resistance in aggressive B-cell lymphoma.
- |||||||||| Remodeling the brain tumor microenvironment by targeting MALT1 to overcome macrophage immunosuppression. (Poster and Exhibition Hall) - Jun 13, 2023 - Abstract #EACR2023EACR_559;
MALT1-PD mice demonstrate a less immunosuppressive TME with an increased M1/M2 macrophage ratio. Further, a similar macrophage phenotype switch in the TME and decrease in GBM tumor growth was observed in mice treated with a MALT1 protease inhibitor, thus confirming a critical role for MALT1 in tumor-induced macrophage reprogramming and GBM progression.ConclusionOur studies nominate MALT1 as a new therapeutic target in GBM whose inhibition could offer dual therapeutic benefit by simultaneously acting in tumor cells and in cells of the TME to impair tumor cell proliferation and survival and reverse tumor-induced immunosuppression.
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