pevonedistat (MLN4924) / Takeda - LARVOL DELTA

Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast percentage AML. (PubMed, Blood Adv) - P3 | "These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of remaining on therapy >3 cycles. (ClinicalTrials.gov, NCT03268954)."

Journal • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia

Beat AML: Study of Biomarker-Based Treatment of Acute Myeloid Leukemia (clinicaltrials.gov) - P2/3 | N=3000 | Recruiting | Sponsor: Beat AML, LLC | Phase classification: P1/2 ➔ P2/3 | Trial completion date: Dec 2028 ➔ Dec 2032 | Trial primary completion date: Dec 2028 ➔ Dec 2032

Biomarker • Phase classification • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • NPM1

A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents. (PubMed, J Hematol Oncol) - P1/2 | "The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML. Trial registration ClinicalTrials.gov (NCT03862157)."

Journal • P1/2 data • P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Renal Disease • CD36 • MCL1 • MECOM • PMAIP1 • TP53

FBXO11 and FBXO32 synergistically activate innate immunity against hepatitis B virus in a NEDD8-dependent manner. (PubMed, Front Immunol) - "Mechanistically, co-immunoprecipitation was used to assess FBXO11/FBXO32 interactions with TRAF3, TBK1, and IRF3, and the NEDD8 inhibitor MLN4924 was applied to confirm NEDD8 dependence...FBXO11 and FBXO32 synergistically enhance antiviral innate immunity by promoting NEDD8-dependent K63-linked TRAF3 ubiquitination, suppressing HBV replication and alleviating immunopathology. These findings reveal a synergistic anti-HBV axis and provide a potential therapeutic strategy."

Journal • Hepatitis B • Infectious Disease • Inflammation • Targeted Protein Degradation • CXCL10 • FBXO11 • FBXO32

Flavokawain A inhibits high glucose-induced malignant progression of lung cancer cells by suppressing PRMT5-mediated PTEN neddylation and nuclear translocation. (PubMed, Oncol Lett) - "Cellular NEDD8 levels were manipulated by overexpressing Flag-NEDD8 and using MLN4924, an inhibitor of NEDD8-activating enzyme. Notably, GSK3326595 exhibited an inhibitory effect similar to that of FKA. The results indicated that FKA suppressed high glucose-induced carcinogenic effects by inhibiting PRMT5-mediated PTEN neddylation and subsequent nuclear translocation."

Journal • Diabetes • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NEDD8 • PRMT5 • PTEN

Neddylation as a molecular integrator of metabolic dysfunction and endothelial dysfunction in type 2 diabetes. (PubMed, Acta Pharmacol Sin) - "Pharmacological modulation of the neddylation pathway, including inhibition of the NEDD8-activating enzyme with MLN4924 (pevonedistat), improves metabolic homeostasis, suppresses inflammatory signaling, enhances antioxidant defenses, and attenuates vascular injury in preclinical studies. In this review, we summarize current advances in neddylation biology, discuss emerging evidence linking dysregulated neddylation to diabetes-associated endothelial dysfunction, highlight critical knowledge gaps, and evaluate the opportunities and challenges of targeting the neddylation pathway for the prevention and treatment of diabetic vascular complications."

Journal • Review • Cardiovascular • Diabetes • Diabetic Retinopathy • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • Retinal Disorders • Targeted Protein Degradation • Type 2 Diabetes Mellitus • HNRNPA2B1 • KDR • NEDD8

MLN4924 Enhances RSL3-Induced Ferroptosis Sensitivity in Glioblastoma via Inhibiting the STAT3/GPX4 Axis. (PubMed, Carcinogenesis) - "The combination of MLN4924 and RSL3 synergistically potentiates ferroptosis and, in vivo, suppresses subcutaneous tumor growth with a considerable biosafety. Collectively, these findings identify GPX4 as the principal mediator of MLN4924-induced ferroptosis and establish that dual targeting of GPX4 transcription and activity represents a promising therapeutic strategy for GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • GPX4 • STAT3

MLN4924 suppresses pancreatic cancer progression and enhances chemosensitivity to gemcitabine by targeting the PTGS2/EGFR-PI3K/Akt/mTOR signaling axis. (PubMed, Anticancer Drugs) - "Notably, both MLN4924 and PTGS2 knockdown significantly enhanced the chemosensitivity of pancreatic cancer cells to gemcitabine. Collectively, our results demonstrate that MLN4924 exerts antitumor effects in pancreatic cancer by targeting the PTGS2-EGFR-PI3K/AKT/mTOR axis, providing a mechanistic rationale for its clinical application in pancreatic cancer therapy."

Journal • Oncology • Palliative care • Pancreatic Cancer • Solid Tumor • CASP3 • MAPK8 • MMP9 • PACERR • PIK3CG • PTGS2

Discovery of spirocyclic amide scaffolds as novel neddylation E1 inhibitors to suppress the growth and survival of lung cancer cells. (PubMed, RSC Med Chem) - "Discovered from a high-throughput screening, followed by structure-guided optimization, compound 24 possesses a distinct spirocyclic amide chemical core entirely different from the clinical-stage NAE inhibitor MLN4924...In A549 xenograft models, it significantly suppresses tumor growth without obvious systemic toxicity. Collectively, 24 (HA-218-6-31-80) represents a promising NAE inhibitor, offering a potential therapeutic candidate for lung cancer and a novel scaffold for neddylation targeted drug discovery."

Journal • Lung Cancer • Oncology • Solid Tumor • CUL1

Evidence that S-phase kinase associated protein 2 (SKP2) is ubiquitinated and degraded via a Rho-related BTB domain containing 1 (RhoBTB1) and Cullin-3 mechanism in placenta. (PubMed, Physiol Rep) - "Two of these, S-Phase Kinase Associated Protein 2 (SKP2) and Rho GTPase-Activating Protein 29 (ArhGAP29), increased in abundance when Cullin activity was blocked by the neddylation inhibitor MLN4924 and co-immunoprecipitated with RhoBTB1...Reanalysis of single cell RNA sequencing data sets revealed that SKP2 exhibits co-expression with RhoBTB1 in SCT precursor cells, SCTs, and cytotrophoblasts. These findings identify SKP2 as a RhoBTB1/CUL3 target in the placenta."

Journal • Targeted Protein Degradation • CHN1 • SKP2

Protein neddylation as a therapeutic target: challenges and opportunities. (PubMed, J Clin Invest) - "In this Review, we systematically summarize the biochemical activity and biological functions of neddylation; its alterations in human diseases, particularly in cancers; and its validation as an attractive target for cancer therapy. We provide an overview on the discovery of neddylation inhibitors and the progress of MLN4924 (pevonedistat) and TAS4464 clinical trials and critically evaluate the core challenges and emerging opportunities for therapeutic strategies targeting neddylation."

Journal • Review • CNS Disorders • Metabolic Disorders • Oncology • Targeted Protein Degradation

Neddylation of NFATc1 and Runx2 regulates osteoclast-osteoblast balance and represents a dual-action therapeutic target for postmenopausal osteoporosis. (PubMed, Exp Mol Med) - "Pharmacological blockade with the NAE1 inhibitor MLN4924 counteracted both effects and, in ovariectomized mice, reduced osteoclast activity while preserving osteoblast function, preventing deterioration of bone mass and microarchitecture. In human PMOP bone tissues, elevated NEDD8 and NAE1 expression was associated with increased NFATc1 in osteoclast-lineage cells and reduced Runx2 in osteoblast-lineage cells, suggesting translational relevance. These findings reveal neddylation as a unifying mechanism that coordinates opposing effects on osteoclast and osteoblast master transcription factors and highlight its potential as a mechanism-driven dual-action therapeutic target."

Journal • Osteoporosis • Rheumatology • NAE1 • NEDD8 • NFATC1 • RUNX2

Neddylation Cooperates with Multiple Phosphorylation to Enhance FGFR1 Stability and Drive Breast Cancer Progression. (PubMed, Exp Cell Res) - "These findings implicate the neddylation-FGFR1 axis as a critical oncogenic pathway in BC. Targeting this pathway represents a promising therapeutic strategy for patients with aberrant FGFR1 expression."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • FGF2 • FGFR1 • NEDD8

Pharmacological inhibition of neddylation by MLN4924 protects against Coxsackievirus B3-induced myocarditis. (PubMed, Biochem Pharmacol) - "MLN4924 attenuated the CVB3-induced loss of eIF4G protein, a change that may contribute to the suppression of CVB3 internal ribosome entry site (IRES)-driven translation and viral protein synthesis. Collectively, our findings support MLN4924 as a promising antiviral candidate for the treatment of VMC."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Inflammation • Oncology • EIF4G1 • NEDD8

Targeting NAE1 suppresses osteoclastogenesis via dual regulation of ferritinophagy and ACSL3-mediated ferroptosis. (PubMed, Autophagy) - "Clinically, serum MUFA levels positively correlated with bone mineral density (r = 0.329, p < 0.05). These findings support MLN4924, a clinical-stage NAE inhibitor, as a potential therapeutic strategy for osteoporosis and define an Nae1-ACSL3-MUFA-ferroptosis axis regulating osteoclast metabolism.Abbreviations: 4-HNE: 4-hydroxynonenal; ACP5/TRAP: acid phosphatase, tartrate resistant; ACSL3: acyl-CoA synthetase long chain family member 3; ACSL4: acyl-CoA synthetase long chain family member 4; BGLAP/OCN: bone gamma-carboxyglutamate protein; BMD: bone mineral density; BMDMs: bone marrow-derived macrophages; BV/TV: bone volume per total volume; CHX: cycloheximide; cKO: conditional knockout; co-IP: co-immunoprecipitation; CTSK: cathepsin K; DFO: deferoxamine; MDS: myelodysplastic syndrome; MUFA: monounsaturated fatty acid; NAE1: NEDD8 activating enzyme E1 subunit 1; NCOA4: nuclear receptor coactivator 4; NEDD8: NEDD8 ubiquitin like modifier; NFE2L2: NFE2 like bZIP..."

Journal • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Osteoporosis • Rheumatology • Targeted Protein Degradation • ACSL3 • ACSL4 • BGLAP • CTSK • NCOA4 • NFATC1 • RUNX2 • SLC40A1 • SLC7A11 • TNFSF11 • TRAP • UBE2M

Identifying Pevonedistat-Based Combinatorial Treatments that Inhibit the Growth of Head and Neck Squamous Cell Carcinoma (AHNS 2026) - "Our unbiased screens identified a number of compounds that demonstrated additive/synergistic effects with pevonedistat in inhibiting HNSCC growth. We validated a number of compounds, including afatinib, that enhanced the ability of pevonedistat to inhibit tumor cell growth. Treatment with pevonedistat sensitized an EGFR-insensitive HNSCC cell line to treatment with the EGFR inhibitor afatinib."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Targeted Protein Degradation

Neddylation-dependent CUL3-KLHL12 E3 ligase drives microglial oxidative stress and neuroinflammation in traumatic brain injury by targeting GCLM for degradation. (PubMed, J Transl Med) - "Our findings characterize the Neddylation-CUL3-KLHL12-GCLM axis as a critical regulator of microglial redox homeostasis and highlight this pathway as a promising therapeutic target for TBI intervention."

Journal • CNS Disorders • Inflammation • Targeted Protein Degradation • Vascular Neurology

NAE inhibitor MLN4924 effectively suppresses Coxsackievirus B3 replication. (PubMed, Microb Pathog) - "In addition to inhibiting the neddylation of viral 3Dpol, upregulated NRF2 also contributes to the antiviral activity of MLN4924. This study demonstrated that targeting neddylation can be a potential antiviral strategy for the treatment of CVB infection."

Journal • Cardiomyopathy • Cardiovascular • Infectious Disease • Inflammation • Targeted Protein Degradation

PEVOLAM: Study to Compare Azacitidine Plus Pevonedistat Versus Azacitidine in Patients With Acute Myeloid Leukemia Not Eligible for Standard Chemotherapy (clinicaltrials.gov) - P3 | N=302 | Active, not recruiting | Sponsor: PETHEMA Foundation | Trial completion date: Jun 2025 ➔ Jul 2026

Trial completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4 • IDH1 • NPM1

CLIP-TAC: A Novel Proteolysis-Targeting Degrader of BCL-XL in Multiple Myeloma (EACR 2026) - "Aims: To overcome thrombocytopenia, a proteolysis-targeting-chimera (PROTAC), called DT2216, was developed that couples navitoclax (BCLXL binder) to a von Hippel–Lindau (VHL) E3 ligase-recruiting ligand to selectively degrade BCLXL in tumour cells, while sparing platelets that lack VHL...Degradation was rescued by pre-treatment with A-1331852 (BCLXL inhibitor) or MLN-4924 (NEDD8-activating enzyme inhibitor), confirming on-target, proteasome-dependent activity...Co-targeting this compensation, either directly with MCL-1 inhibitor AMG-176 or indirectly with cyclin-dependent kinase inhibitors (CYC065, THZ1, Samuraciclib), synergistically enhanced DT2216-induced cell death... MM exhibits heterogeneous dependence on BCL-2 family proteins. BH3-profiling can identify BCLXL-reliant tumours. Targeted degradation of BCLXL with DT2216, or a novel Clip-TAC, shows therapeutic potential in MM."

Hematological Malignancies • Multiple Myeloma • Plasmacytoma • Targeted Protein Degradation • Thrombocytopenia • Von Hippel-Lindau Syndrome • BCL2 • BCL2L1

Beyond Neddylation Inhibition: X‑ray Structures Reveal Carbonic Anhydrase Isoform Selectivity of Pevonedistat. (PubMed, ACS Med Chem Lett) - "These findings provide a mechanistic explanation for the known preferential partitioning of pevonedistat into whole blood via binding to erythrocyte CAs and suggest that CA inhibition may contribute to its antitumor activity in hypoxic tumor microenvironments where hCA IX and XII are overexpressed. This study reveals a dual functional profile for pevonedistat, linking neddylation inhibition with selective targeting of tumor-associated CAs and offers to exploit this synergy in anticancer drug design."

Journal • Oncology • CA9

TARGETING DCN1 OVERCOMES DELETERIOUS EFFECTS OF BROAD NEDDYLATION INHIBITION AND ENABLES FETAL HEMOGLOBIN INDUCTION IN SICKLE CELL DISEASE (EHA 2026) - "Pan-neddylation inhibition using MLN4924 or knockout of ubiquitin conjugating enzyme E2M (UBE2M) or Cullin 3 (CUL3) induced HbF accompanied with cytotoxicity...Summary/Conclusion In summary, we identified DCN1 as a novel target for the treatment of SCD, and discovered a first-in-class inhibitor, CLY-124, that induces HbF without cytotoxicity as monotherapy and shows synergy with hydroxyurea. At pharmacologically active doses in preclinical studies, CLY-124 exhibited a favorable safety profile with no observed toxicities or cytopenias. CLY-124 is being evaluated in a first-in-human study assessing safety, pharmacokinetics, and HbF induction in healthy volunteers and participants with SCD."

First-in-human • Gene Therapies • Genetic Disorders • Sickle Cell Disease • Targeted Protein Degradation • CD34 • UBE2M

RAD51 INHIBITION SYNERGIZES WITH MLN4924 BY DISABLING HOMOLOGOUS RECOMBINATION AND ACTIVATING CGAS–STING–MEDIATED INNATE IMMUNITY IN ACUTE MYELOID LEUKEMIA (EHA 2026) - "In vivo, MLN4924/RI-1 suppressed AML xenograft growth more effectively than either monotherapy without overt toxicity and increased T-cell infiltration and cytotoxic phenotypes in PBMC-reconstituted xenografts; these effects were attenuated in STING-deficient settings. Summary/Conclusion RAD51 inhibition potentiates MLN4924 by concurrently disabling HRR-mediated DNA repair and activating cGAS–STING–driven innate immune signaling, providing a mechanistic and translational rationale for this combination strategy in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • HRD • PD-L1 • RAD51 • STING

Protein Neddylation Beyond Tumor Cells is a Vital Modulator of Anticancer Immunity. (PubMed, Phenomics) - "MLN4924, a potent NAE inhibitor, has emerged as a promising anti-cancer agent based on neddylation interference...This understanding indicates that targeting neddylation could potentially be combined with immunotherapies for more effective treatment strategies. Here, we briefly outline how neddylation is organized and its modulatory roles in both tumor cells and intertumoral immune cells, proposing an optimistic outlook for neddylation-targeted therapy."

Journal • Review • Oncology • Targeted Protein Degradation • NEDD8

Pevonedistat, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=53 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Dec 2026 ➔ Dec 2027 | Trial primary completion date: Jun 2026 ➔ Dec 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology