ONX 0914 / Protalex, Amgen - LARVOL DELTA

Targeting immunoproteasome-dependent β-catenin degradation as a therapeutic strategy in Relapsed/Refractory acute lymphoblastic leukemia (ASH 2025) - "Interestingly, treatment with M3258 (a selective PSMB8 inhibitor) did not interfere with β-cateninprotein degradation, suggesting that combined inhibition of both PSMB8 and PSMB9 is required forefficient inhibition...Likewise, genetic deletion of LEF1 rescued cellviability and caused resistance to Zetomipzomib and ONX-0914, highlighting the importance ofrepressive LEF1/β-catenin complexes in B- and T-ALL cells to suppress MYC. Our findings uncovered a previously unrecognized dependency of B- and T-ALL cells onimmunoproteasome-mediated β-catenin degradation to sustain MYC expression and survival... Our findings uncovered a previously unrecognized dependency of B- and T-ALL cells onimmunoproteasome-mediated β-catenin degradation to sustain MYC expression and survival. Targetingthe immunoproteasome, rather than the generic proteasome, offers a more selective strategy forlymphoid malignancies, with the potential for reduced off-target toxicity compared to..."

Acute Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Solid Tumor • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • T-cell Acute Lymphoblastic Lymphoma • CTNNB1 • MYC • PSMB10 • PSMB5 • PSMB8 • PSMB9 • TCF7

Targeting β-catenin nuclear export and protein degradation in high-risk acute lymphoblastic leukemia (ASH 2025) - "The combination of Selinexorwith GSK3B inhibition (LY2090314) or PSMB8/PSMB9 inhibition (Zetomipzomib/ONX0914) resulted insynergistic nuclear β-catenin accumulation in reporter cells...The identification of β-catenin as an XPO1 cargo protein and thenucleus as a shelter from protein degradation provide a mechanistic rationale for combining XPO1inhibition (selinexor, eltanexor) with GSK3B or immunoproteasome inhibition, which will support thedesign of forthcoming in vivo studies, including xenograft-based preclinical efficacy models in patient-derived B- and T-ALL xenografts. These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL... These findings identify β-catenin as a previously unrecognized and functionally significantcargo protein of XPO1 in B- and T-ALL. Our finding supports a promising combinatorial strategy for thetreatment of r/r ALL by co-targeting nuclear export and β-catenin protein..."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • PSMB8 • PSMB9 • XPO1

Immunoproteasome inhibition triggers protein stress and apoptosis in cells of B cell lineage without impairing vaccination-induced antibody responses. (PubMed, Cell Death Discov) - "In this study, we used ONX 0914, an LMP7/LMP2-selective inhibitor of the IP, to study the effect of IP inhibition on B cells and antibody production...Furthermore, IP inhibition neither impaired vaccine-induced antibody responses, nor affected different B cell populations in two different vaccination models. These findings suggest that IP inhibition does not compromise vaccination efficacy and anti-viral humoral immunity, supporting the potential of IP-targeted therapies for autoimmune diseases."

Journal • Preclinical • B Cell Lymphoma • Hematological Malignancies • Immunology • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Targeted Protein Degradation • IFNG • PSMB8

Key features of the innate immune response is mediated by the immunoproteasome in microglia. (PubMed, Sci Rep) - "Moreover, we show that the immunoproteasome regulates the degradation of IκBα, a modulator of NF-κB signaling. Finally, we demonstrate that NADH prevents induction of the immunoproteasome, representing a potential pathway to suppress immunoproteasome-dependent immune responses."

Journal • Inflammation • IFNG • NFKBIA

High-throughput screening and meta-analysis for lead compounds in antimalarial drug discovery. (PubMed, Malar J) - "Combining HTS and meta-analysis provides a robust method for screening antimalarial candidate compounds and identifying new hits with in vivo activity as candidates to treat drug-resistant malarial strains."

Journal • Retrospective data • Infectious Disease • Malaria

Immunoproteasomes in Skeletal Muscle Pathologies: Emerging Roles, Conflicting Evidence, and Future Directions. (PubMed, Cells) - "Selective IMP inhibitors, such as ONX 0914 and KZR-616, display potent anti-inflammatory effects in preclinical models of autoimmune myositis and muscle atrophy. We emphasize the need for a deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology and strategies combining selective inhibitors to enhance therapeutic efficacy while minimizing adverse effects. IMPs thus represent both a promising and potentially risky therapeutic target, with outcomes highly dependent on disease context."

Journal • Review • Immunology • Inflammation • Muscular Atrophy • Muscular Dystrophy • Myositis • Sarcopenia

Immunoproteasome Inhibition Positively Impacts the Gut-Muscle Axis in Duchenne Muscular Dystrophy. (PubMed, J Cachexia Sarcopenia Muscle) - "Our study advances the understanding of the role of dysbiosis in DMD disease and identifies IP inhibition as a potential therapeutic strategy to modulate the dystrophic gut-muscle axis, offering new perspectives for microbiota-targeted therapies."

Journal • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Muscular Dystrophy • Transplantation • CCL2 • CD68 • MRC1 • PSMB8 • PSMB9 • TGFB1 • TNFA

Dual-targeting proteasome inhibitor ONX-0914 demonstrates potent antiplasmodial activity for malaria treatment. (PubMed, Int J Parasitol Drugs Drug Resist) - "Notably, ONX-0914 strongly inhibited the proliferation of various Plasmodium falciparum strains, including chloroquine (CQ)- and artesunate (ART)-sensitive and -resistant strains, with a low nanomolar IC50 (20,960 h∗μg/ml, T1/2 = 7.9 h [IV], 0.7 h [PO], C max = 10708.2 μg/ml [PO], bioavailability = 23.83 %), supporting its antimalarial efficacy. Owing to its low toxicity, robust antiplasmodial activity through a combination mechanism, and supportive pharmacokinetic properties, ONX-0914 is a promising antimalarial agent."

Journal • Immunology • Infectious Disease • Malaria • Oncology • Targeted Protein Degradation

Current landscape of the immunoproteasome: implications for disease and therapy. (PubMed, Cell Death Discov) - "While β5i-specific inhibitors (e.g., ONX 0914) show therapeutic potential in preclinical models by mitigating proteotoxicity and inflammation, the immunoproteasome's dual roles-cytoprotective or pathogenic-are context-dependent, necessitating precise targeting strategies. This review synthesizes recent advances in immunoproteasome biology, disease mechanisms, and therapeutic prospects, while highlighting unresolved questions on subunit specificity and microenvironmental regulation."

Journal • Review • Cardiovascular • CNS Disorders • Immunology • Inflammation • Metabolic Disorders

Highly specific Immunoproteasome inhibitor M3258 induces proteotoxic stress and apoptosis in KMT2A::AFF1 driven acute lymphoblastic leukemia. (PubMed, Sci Rep) - "Proteasome inhibitors (PIs) bortezomib, carfilzomib and ixazomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have clinical activity in acute lymphoblastic leukemia (ALL). Treatment of KMT2A::AFF1 ALL cells with M3258, ONX-0914, and bortezomib induced proteotoxic stress that was prevented by the protein synthesis inhibitor cycloheximide, which dramatically desensitized cells to PI-induced apoptosis. Thus, similar to multiple myeloma, ALL cells are sensitive to PIs and IPIs due to increased proteotoxic stress caused by elevated rates of protein synthesis."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Targeted Protein Degradation • AFF1 • KMT2A

Targeting the ubiquitin-proteasome pathway in systemic lupus erythematosus. (PubMed, Expert Rev Clin Immunol) - "Bortezomib and the selective immunoproteasome inhibitors, ONX-0914 and zetomipzomib, ameliorate renal disease in murine lupus models...Thalidomide and lenalidomide are effective in refractory cutaneous lupus but again limited by their off-target effects. A phase II RCT of iberdomide shows favorable results in SLE, especially chronic and subacute cutaneous lesions. These molecules should be further explored in larger clinical trials of renal and cutaneous SLE."

Journal • Review • Cutaneous Lupus Erythematosus • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Systemic Lupus Erythematosus • Targeted Protein Degradation • CRBN

Degradation of IL-4Ralpha by Immunoproteasome: implication in airway type 2 inflammation and hyperresponsiveness. (PubMed, Front Immunol) - "This study was aimed to determine how IP regulates type 2 inflammation and AHR using LMP7 (a subunit of IP) deficient mouse lungs, precision-cut lung slices (PCLS), and cultured human airway epithelial cells treated with IL-13 in the absence or presence of an IP inhibitor ONX-0914 or exogenous IP...Collectively, these data demonstrated that IP promotes degradation of IL-4Rα, while inhibits type 2 inflammation and AHR. Enhancement of IP expression or activity may serve as an alternative approach to reduce the severity of type 2 inflammation and AHR."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • IFNG • IL13 • IL4R • PSMB8

CGRPβ suppresses the pathogenesis of ulcerative colitis via the immunoproteasome. (PubMed, Sci Rep) - "Treatment with ONX-0914, an immunoproteasome inhibitor, markedly improved these symptoms, highlighting the role of the immunoproteasome in exacerbating UC...Our findings suggest that functional differences in CGRP isoforms may influence the severity and management of UC. This insight into the neuro-immune mechanism of UC opens avenues for novel therapies that address both the neural and immune aspects of this disease."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

Immunoproteasome inhibition reduces donor specific antibody production and cardiac allograft vasculopathy in a mouse heart transplantation model. (PubMed, Front Transplant) - "Recipients were treated with alemtuzumab (10 µg, IP) on days -2, -1, 2, and 4 and anti-CD25mAb (PC61, 100 µg, IP) on day 7 to accelerate AMR with or without IPI (ONX-0914,15 mg/kg, SQ), administered on transplant day and three times a week thereafter. However, IPI-resistant DSA production was also observed and increased mortality with IPI therapy raises concerns about potential toxicity. Further investigation is warranted to assess the utility and potential risk associated with the use of IPI as a post-transplant maintenance immunosuppression."

Journal • Preclinical • Antibody-mediated Rejection • Cardiovascular • Transplantation

Effects of immunoproteasome inhibition on acute respiratory infection with murine hepatitis virus strain 1. (PubMed, J Virol) - "IP inhibition using ONX-0914 did not affect MHV-1 replication in bone marrow-derived dendritic cells in vitro...Inhibition of immunoproteasome activity did not affect MHV-1 replication but increased MHV-1-induced weight loss, mortality, and inflammation in lungs and livers. Thus, our findings indicate that the immunoproteasome is a critical protective host factor during coronavirus respiratory infection."

Journal • Preclinical • Hepatology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Otorhinolaryngology • Pneumonia • Respiratory Diseases • Targeted Protein Degradation • IFNB1 • IFNG • TNFA

Targeting Immunoproteasome in Polarized Macrophages Ameliorates Experimental Emphysema Via Activating NRF1/2-P62 Axis and Suppressing IRF4 Transcription. (PubMed, Adv Sci (Weinh)) - "Intriguingly, ONX-0914 inhibited M1 polarization through the nuclear factor erythroid 2-related factor-1 (NRF1) and NRF2-P62 axis, while the suppression of M2 polarization is regulated by inhibiting the transcription of interferon regulatory factor 4 (IRF4). In summary, the findings suggest that targeting immunoproteasome in macrophages holds promise as a therapeutic strategy for COPD."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • ELANE • IRF4 • NRF1 • PSMB8

Enhancing the immunogenicity of Wilms tumor 1 epitope in mesothelioma cells with immunoproteasome inhibitors. (PubMed, PLoS One) - "These results suggest that ONX-0914 prevents the internal destructive cleavage of WT1235 by IP, thereby promoting the specific presentation of the WT1 epitope by MESO-4. In conclusion, selective IP inhibitors might offer a means to modulate cancer cell immunogenicity by directing the presentation of particular tumor epitopes."

Journal • Malignant Pleural Mesothelioma • Mesothelioma • Nephrology • Oncology • Solid Tumor • Wilms Tumor • CD8 • WT1

Targeting the immunoproteasome in hypothalamic neurons as a novel therapeutic strategy for high-fat diet-induced obesity and metabolic dysregulation. (PubMed, J Neuroinflammation) - "Our findings strongly support the pathogenic involvement of the immunoproteasome in hypothalamic neurons in the context of HFD-induced obesity and metabolic disturbances. Targeting the immunoproteasome highlights a promising therapeutic strategy to mitigate the detrimental effects of obesity on the insulin-glucose axis and cellular homeostasis. This study provides valuable insights into the mechanisms driving obesity-related metabolic diseases and offers potential avenues for developing novel therapeutic interventions."

Journal • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • PTEN

Geraniol (GER) attenuated chronic sleep restriction (CSR)-induced neuroinflammation in adolescent mice. (PubMed, J Neuroimmunol) - "ONX-0914 was applied to inhibit LMP7 selectively, and data validated that GER might alleviate CSR-induced neuroinflammation by regulating LMP7. Our study provides evidence that LMP7 is a critical regulator of CSR-induced proinflammation, and geraniol might be a promising therapy against CSR-induced neurodevelopmental disorders."

Journal • Preclinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Inflammation • Mood Disorders • Psychiatry • IL1B • PSMB8 • TNFA

Immunoproteasome Inhibits Airway Type 2 Inflammation in Part Through the Degradation of IL4-Ralpha (ATS 2024) - "These cells were then pre-treated with ONX-0914 (100nM), an inhibitor of IP subunit LMP7, and then stimulated with 10ng/ml of IL-13... The immunoproteasome may inhibit type 2 inflammation airway contraction through the degradation of IL-4Ra. Enhancing immunoproteasome expression or function may serve as a new therapeutic approach in attenuating allergic inflammation in asthma. Research Funding Source: R01AI150082"

Asthma • Inflammation • Pulmonary Disease • Respiratory Diseases • IL13 • IL4 • IL4R • PSMB8

The role of the immunoproteasome in cardiovascular disease. (PubMed, Pharmacol Res) - "Furthermore, the immunoproteasome also serves nonimmune functions, such as maintaining protein homeostasis and regulating signalling pathways, and is involved in the pathophysiological processes of various cardiovascular diseases (CVDs). This review aims to provide a comprehensive summary of the current research on the involvement of the immunoproteasome in cardiovascular diseases, with the ultimate goal of identifying novel strategies for the treatment of these conditions."

Journal • Review • Cardiovascular • Targeted Protein Degradation

Immunoproteasome Inhibition Reduces Donor-Specific Antibody Production and Cardiac Allograft Vasculopathy in a Mouse Heart Transplantation Model (ATC 2024) - "Recipients were treated with alemtuzumab (10μg, IP, on days -2, -1, 2, and 4 and anti-CD25mAb (PC61 clone, 100μg, IP) on day 7 to accelerate AMR development with or without IPI, ONX-0914 (15mg/kg, SC), administered on transplant day and three times a week thereafter. This study demonstrated the efficacy of ONYX-194, an IPI, in controlling post-transplant DSA production and the onset of CAV in a murine heart transplant model. However, the increased mortality in IPI-treated group raises concerns about potential IPI toxicity. Therefore, further investigation is warranted to assess the utility and potential risk associated with the use of IPI as a post-transplant maintenance immunosuppression."

Preclinical • Antibody-mediated Rejection • Cardiovascular • Fibrosis • Immunology • Solid Organ Transplantation • Transplantation

Immunoproteasomal Inhibition With ONX-0914 Attenuates Atherosclerosis and Reduces White Adipose Tissue Mass and Metabolic Syndrome in Mice. (PubMed, Arterioscler Thromb Vasc Biol) - "Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • Metabolic Disorders • APOE • PSMB8

Immunoproteasomal Processing of IsoLG-Adducted Proteins Is Essential for Hypertension. (PubMed, Circ Res) - "The role of the proteasome and the immunoproteasome in Ang II (angiotensin II)-induced hypertension was studied in C57BL/6 mice treated with bortezomib or the immunoproteasome inhibitor PR957 and by studying mice lacking 3 critical immunoproteasome subunits (triple knockout mouse). These studies define a previously unknown role of the immunoproteasome in DCs and ECs in CD8+ T cell activation. The immunoproteasome in DCs and ECs is critical for isoLG-adduct presentation to CD8+ T cells, and in the endothelium, this guides homing and infiltration of T cells to specific tissues."

IO biomarker • Journal • Cardiovascular • Hypertension • Inflammation • CD8 • PSMB8 • STING • TLR7

Cold Storage Followed by Transplantation Induces Immunoproteasome in Rat Kidney Allografts: Inhibition of Immunoproteasome Does Not Improve Function. (PubMed, Kidney360) - "These results suggest that the pharmacological inhibition of immunoproteasome function during CS does not improve graft function or outcome. In light of these findings, future studies targeting immunoproteasomes during both CS and transplantation may define the role of immunoproteasomes on short- and long-term kidney transplant outcomes."

Journal • Preclinical • Transplantation