pevonedistat (MLN4924) / Takeda - LARVOL DELTA

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

Validation of the international working group (IWG) 2023 criteria for clinical benefit in higher risk Myelodysplastic Syndromes (HR-MDS) using a large, international, randomized Phase 3 clinical trial dataset (ASH 2025) - "Here we sought to examine theprognostic impact of the IWG 2023 criteria, especially CR and composite (cCR), in the phase III PANTHERtrial dataset which compared azacitidine (AZA) + pevonedistat vs. AZA alone in patients with HR-MDS,CMML, and oligoblastic AML (Ades L Blood Advances 2022). We show that achieving cCR per IWG 2023 response criteria is associated with a significantimprovement in OS in a large prospective clinical trial for patients treated homogenously with azacitidinemonotherapy, with only 7.4% of patients receiving subsequent allo-SCT. Importantly, no patients had PRas their best response, which is in line with prior observations that PR is rare and often a transientresponse that converts to CR with continued therapy. Our data supports the inclusion of cCR as ameasure of meaningful clinical benefit in clinical trials of HR-MDS."

Clinical • P3 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • TP53

Identification of NAE1-dependent β-catenin neddylation as selective vulnerability in B-cell malignancies (ASH 2025) - "Importantly, both pevonedistat and TAS4464 strongly synergized with the GSK3B inhibitorLY2090314 in patient-derived B-ALL, mantle cell lymphoma and CLL samples.Conclusion. Based on CRISPR-screens, we discovered a novel B-cell-selective high-efficiency complex forβ-catenin protein degradation, which depends on NAE1-dependent neddylation. Given the surprising B-cell-selectivity of this mechanism, our findings support a rationale to repurpose clinically tested NAE1-inhibitors for the treatment of refractory B-cell malignancies as single agent or in combination withGSK3B inhibitors."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • Targeted Protein Degradation • ABL1 • AXIN1 • BCR • CTNNB1 • FBXO11 • MYC • PTPRC • UBA3

Mechanistic study of the Cullin3-CRL3^KEAP1-NRF2 neddylation axis in chemotherapy resistance of Acute Myeloid Leukemia stem cells (ASH 2025) - "The specific strategies included: ① Establishing an Ara-C gradient resistance model andintervening with the NAE inhibitor MLN4924 to assess LSC survival, ROS levels, and mitochondrialmembrane potential; ② Employing high-sensitivity NEDD8 mass spectrometry and Co-IP to identify theneddylation sites of Cullin3 and its interaction dynamics with KEAP1 post-chemotherapy; ③ Constructinga KEAP1-NRF2 dual fluorescence reporter system to track NRF2 nuclear translocation in real-time underoxidative stress; ④ Using CRISPR-Cas9 to mediate a Cullin3-KR (K712R) mutation to block its neddylationand verify the integrity of the axis on downstream expression of ALDH1A1, ABCB1, and BCL-2; ⑤ Utilizingflow cytometry to detect LSC apoptosis and ROS probes to monitor redox balance; ⑥ Evaluating the invivo synergistic efficacy and survival benefit of MLN4924 combined with Ara-C in NSG mousetransplantation models. This studyreveals for the first time that the chemotherapy-induced..."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Solid Tumor • Targeted Protein Degradation • ABCB1 • ALDH1A1 • BCL2 • CD38 • KEAP1

Cly-124, a first-in-class DCN1 inhibitor partially suppresses CUL3 neddylation and induces fetal hemoglobin is a new potential treatment for sickle cell disease (ASH 2025) - "Despite demonstrated efficacy, access to this therapy remains limited due tomanufacturing complexity, toxicities of busulfan conditioning, and high cost, especially for individuals inlow and middle income countries...Pan-neddylation inhibitor MLN4924 or genetic knockout ofubiquitin conjugating enzyme E2 M (UBE2M) or Cullin 3 (CUL3) induced >25 % HbF (p<0.0001), but causederythroid toxicity and lineage skewing...CLY-124, is a first-in-class DCN1inhibitor with potent HbF induction as monotherapy and in synergy with hydroxyurea, through a non-cytotoxic and non-epigenetic mechanism. Pre-clinical toxicology studies of CLY-124 demonstrated a safeprofile with no hematological toxicity, major organ dysfunction, or laboratory abnormalities at clinically-relevant exposures. CLY-124 has begun dosing in a first-in-human study that will assess safety, PK, andHbF in healthy volunteers and participants with SCD."

Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Targeted Protein Degradation • CD34 • HBG1 • UBE2M

Genome-wide CRISPR screening identifies CRL1 as a therapeutic target for restoring CD19 expression and improving immunotherapy efficacy in B-cell malignancies (ASH 2025) - "Immune cytotoxicitywas quantified using flow based assays in cocultures with CAR-T cells, CAR-NK cells, and CD16⁺ NKeffectors combined with the therapeutic CD19 monoclonal antibody Tafasitamab for antibody dependentcellular cytotoxicity (ADCC). Our study identifies CRL1 as a novel post-translational regulator of CD19 protein stability, withimplications for immune escape in B cell malignancies. Pharmacologic inhibition of CRL1 throughpevonedistat stabilises CD19 and significantly enhances immune cytotoxicity mediated by CAR-T cells,CAR-NK cells, and antibody dependent effector mechanisms. These findings pave the way to overcomeantigen escape and enhance CD19 targeted immunotherapies in resistant or relapsed B-cell leukemiasand lymphomas.This research was supported by the grant from Czech Science Foundation (project no."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Targeted Protein Degradation • CD19 • CUL1

The core role of exosomal mir-21-5p/TGF-β1-CXCL12/RANKL axis in bone marrow microenvironment remodeling in multiple myeloma and targeted intervention strategies (ASH 2025) - "In a study involving NSG mice with5TGM1-BR tumors, the combination of bortezomib administered at a dose of 0.5 mg kg⁻¹ twice weeklyand MLN4924-antagomiR liposomes at 2 mg kg⁻¹ weekly resulted in a notable reduction of tumorbioluminescence imaging (BLI) flux from 1.1 × 10⁷ to 3.2 × 10⁶ photons s⁻¹, and it also extended themedian survival of the mice from 34 to 71 days (p < 0.001). These findings suggest that multiple myeloma (MM)exosomes play a crucial role in remodeling the bone marrow niche through the miR-21-5p/TGF-β1–CXCL12/RANKL signaling axis, which drives the conversion of cancer-associated mesenchymal stem cells(CA-MSC), osteolysis, and resistance to proteasome inhibitors. Therefore, targeting this exosome-mediated pathway presents a promising strategy for overcoming drug resistance and improvingconditions associated with MM-related bone disease."

Hematological Malignancies • Multiple Myeloma • CD63 • CD81 • CXCL12 • FAP • MIR21 • TGFB1

The impact of histone deacetylase inhibition on neurobehavioural outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review. (PubMed, Front Immunol) - "Valproate was the most frequently studied HDAC inhibitor (n=20), followed by 4-phenylbutyrate (4-PBA; n=7) and RGFP966 (n=3). Trichostatin A, tubastatin A, entinostat, PCI-34051, scriptaid, CI-994, TMP269, vorinostat, 3-TYP, SW-100 and ACY1215 were each evaluated in a single study. Three studies used the sirtuin-1 (HDAC class III) inhibitor EX527 administered with an activator molecule: melatonin (n=1), MLN4924 (n=1) and oxymatrine (n=1)...These results support further investigation of HDAC inhibitors in preclinical studies before translation into clinical trials. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023477882."

Journal • Preclinical • Review • CNS Disorders • Orthopedics • Pain • Psychiatry • Reperfusion Injury • SIRT1

Phase I study of pevonedistat combined with capecitabine and oxaliplatin in patients with platinum-refractory advanced gastric cancer. (PubMed, Sci Rep) - "Median overall survival was 9.3 months and progression-free survival was 4.4 months. Pevonedistat plus CapeOX was well tolerated and showed promising efficacy as salvage-line chemotherapy for AGC."

Journal • P1 data • Gastric Cancer • Oncology • Solid Tumor

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 primary completion date: Oct 2026 ➔ Jun 2026

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

Deciphering glioblastoma heterogeneity: Integrating molecular signatures and genomic landscapes to predict drug sensitivity and advance precision oncology (SNO 2025) - "Comprehensive drug screening was performed on these models, evaluating agents such as temozolomide, arsenic trioxide (ATO), TRC102, pevonedistat, TAS4464, candesartan cilexetil, selinexor, GB13, DSP-0390, and the combination of ATO with a MNK1 inhibitor. Future research will focus on analyzing CNV changes and transcriptomic differential expression within patient data and validating drug efficacy on patient-derived tumor cultures. This comprehensive strategy aims to translate preclinical discoveries into clinically relevant biomarkers, ultimately paving the way for personalized and more effective GBM treatments."

Heterogeneity • Brain Cancer • Glioblastoma • Solid Tumor

NCI-2018-00315: Pevonedistat and Ibrutinib in Treating Participants With Relapsed or Refractory CLL or Non-Hodgkin Lymphoma (clinicaltrials.gov) - P1 | N=18 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Nov 2025 ➔ Nov 2026 | Trial primary completion date: Nov 2025 ➔ Nov 2026

Trial completion date • Trial primary completion date • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prolymphocytic Leukemia • Richter's Syndrome • Small Lymphocytic Lymphoma • Waldenstrom Macroglobulinemia • CCND1 • FCER2

Discovery of a Proteolysis Targeting Chimera for TRKA and RET-derived oncoproteins. (PubMed, Sci Rep) - "Mechanistically, TPM3-TRKA degradation by compound 9 was dependent on CRBN-mediated polyubiquitination and proteasomal degradation; accordingly, it was hindered by inhibitors of the proteasome (MG132) or Cullins (MLN4924), by dominant negative Cullin 4A mutant, and by free pomalidomide. Finally, a compound 9 derivative, compound 20, induced in vivo degradation of TMP3-TRKA in KM12 cells mouse xenografts. In conclusion, our study indicated that PROTAC-mediated degradation is an efficient strategy to intercept RET and TRKA oncogenic signaling."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CCDC6 • CRBN • CUL4A • RET • TPM3

SUMOylation and NEDDylation in kidney diseases. (PubMed, Exp Mol Pathol) - "Accumulated studies display the therapeutic effect of the activators and inhibitors of SUMOylation and NEDDylation against kidney diseases, such as TAK-981 and MLN4924. Therefore, SUMOylation and NEDDylation function as promising therapeutic targets for kidney diseases, and their activators and inhibitors may serve as novel candidates."

Journal • Review • Cardiovascular • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • Targeted Protein Degradation • HIF1A • NOTCH1 • RHOA • STAT1 • STK11

Deciphering glioblastoma heterogeneity: Integrating molecular signatures and genomic landscapes to predict drug sensitivity and advance precision oncology (WFNOS 2025) - "Comprehensive drug screening was performed on these models, evaluating agents such as temozolomide, arsenic trioxide (ATO), TRC102, pevonedistat, TAS4464, candesartan cilexetil, selinexor, GB13, DSP-0390, and the combination of ATO with a MNK1 inhibitor. Future research will focus on analyzing CNV changes and transcriptomic differential expression within patient data and validating drug efficacy on patient-derived tumor cultures. This comprehensive strategy aims to translate preclinical discoveries into clinically relevant biomarkers, ultimately paving the way for personalized and more effective GBM treatments."

Heterogeneity • Brain Cancer • Glioblastoma • Glioma • Solid Tumor

EA2187: Testing the Combination of Pevonedistat With Chemotherapy for Bile Duct Cancer of the Liver (clinicaltrials.gov) - P2 | N=40 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Biliary Cancer • Cholangiocarcinoma • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CD4

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 primary completion date: Oct 2025 ➔ Oct 2026

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

Neddylation: from regulatory mechanisms to clinical implications in cancer. (PubMed, J Adv Res) - "This review constructs a multi-dimensional pathogenic network of neddylation at a systematic level, providing a comprehensive elaboration of its molecular basis in governing key cancer characteristics through modulating protein functions and cellular activities. Simultaneously, we focus on targeted therapeutic strategies against this pathway, analyzing the clinical potential and future directions of novel cancer treatment approaches based on preclinical and clinical evidence from inhibitors such as MLN4924 and TAS4464."

Journal • Review • Oncology

Multiomic Characterization of Myelodysplastic Neoplasms (MDS) with Micromegakaryocytes Highlights the Role of EZH2-RUNX1 deregulation in Disease Physiopathology and Response to Targeted Therapies (ASH 2023) - "Finally, activity of investigational drugs including 5-azacytidine, lenalidomide, venetoclax, rigosertib and pevonedistat, was evaluated in MEG01-activated cells and in vivo using a chicken embryo chorioallantoic membrane (CAM) model of MDS patient-derived xenograft (PDX). Thus, this phenomenon may be considered as a characteristic feature of MDS cases with an elevated proportion of micro-MK. Of note, preliminary in vitro and in vivo results support the use of venetoclax for the treatment of this subgroup of patients with dismal outcome."

Hematological Malignancies • Myelodysplastic Syndrome • Oncology • ASXL1 • DDX41 • ITGA2B • ITGB3 • RUNX1 • SF3B1 • SRSF2 • STAG2 • TET2 • U2AF1 • ZRSR2

Phase 1b/2 Study of Escalating Doses of the NEDD8 Activating Enzyme Inhibitor Pevonedistat Administered in Combination with Standard Induction Therapy (Cytarabine and Idarubicin) in Newly Diagnosed High Risk Acute Myeloid Leukemia (ASH 2023) - P1/2 | "Pevonedistat in combination with cytarabine and idarubicin was well tolerated among adults with newly diagnosed, high-risk AML and induced deep remissions with promising RFS and OS."

Combination therapy • P1/2 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Renal Disease • Transplantation • ATF3 • SLC7A11

High-Throughput Screens Identify NEDD8 Inhibition As a Strategy to Augment Natural Killer Cell Cytotoxicity Against Blood Cancers (ASH 2023) - "In conclusion, we discovered a cell context-specific synergy between pevonedistat and NK cells, which increased NK cell cytotoxicity against malignant cells in vitro. In addition, our results demonstrate the potential of using a high-throughput platform for studying NK cell-drug interactions against malignant cells, while aiming to improve treatment for hematological malignancies through combination immunotherapies."

IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Myeloid Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • CXCL8 • IFNG • IL10 • IL1B • IL2 • IL6 • NQO1 • SLC7A11 • TNFA • TNFRSF1B

Transcriptomics and Time-Course Proteomics Reveal Pclaf As an Inducer of Resistance Against Pevonedistat in Diffuse Large B-Cell Lymphoma (ASH 2023) - "The resistance to Pevonedistat was authenticated by resistance index and its specificity was substantiated by cross resistance test to its downstream proteasome inhibitors, MG132 and Bortezomib...Given PCLAF functions in DNA damage repair, via drug library screening, we found a DNA damage repair inhibitor, Niraparib tosylate, significantly ameliorated DLBCL cells' resistance against Pevonedistat. The efficacy of combination was validated both in vitro and in vivo. In conclusion, this study identified that PCLAF overexpression mediated the resistance against Pevonedistat in DLBCL and proposed a potential combination strategy to improve Pevonedistat resistance."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • PCLAF • PCNA

Activation of Autophagy Via the SQSTM1-KEAP1-NRF2 Axis Induced By Pevonedistat Provides a Temporary Readjustment of MDS/AML Cells Leading to the Development of Resistance (ASH 2024) - P2 | "The standard treatment for high-risk MDS is inhibition of DNA methyltransferase with 5-azacytidine (AZA). This allows mutagenesis to occur which results in complete loss of PEVO responsiveness possibly via mutating UBA. Thus, the SQSTM1-KEAP1-NRF2 pathway appears to be a major checkpoint during the treatment of MDS with PEVO and could stay behind the loss of therapeutic efficacy in MDS patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • KEAP1 • NEDD8 • SQSTM1

Targeting β-Catenin Protein Degradation in Refractory B-Cell Malignancies (ASH 2024) - "Background and Significance : Approaches for targeted elimination of B-cells as the root-cause of disease have been highly effective in the treatment of B-cell malignancies (rituximab, ibrutinib)...Most notably, among 4,518 compounds screened, we identified 9 top-ranking compounds that converge on targeting the β-catenin protein degradation pathway : GSK3B-inhibitors (AZD7969, LY2090314, GSK3i IV, CHIR99021, ML320), the neddylation-activating enzyme (NAE)-inhibitor pevonedistat and proteasome inhibitors (MG-132, Bortezomib, Ixazomib) showed high B-cell-selectivity along with known B-cell-selective drugs such as dexamethasone and ibrutinib...Conclusion : This study reveals a previously unrecognized targetable dependency of B-cell malignancies on β-catenin protein degradation that is amenable to near-term evaluation in patients with refractory disease. The discovery of GSK3B-dependent β-catenin protein degradation as unique B-lymphoid vulnerability provides a rationale to..."

B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation • CTNNB1 • IKZF1 • TCF7

Primary Hematopoietic Cells of Vexas Patients Are Highly Sensitive to Treatment with TAK-243 and Pevonedistat (ASH 2024) - "With our results we hypothesize that the application of targeted inhibitors of UBA1, such as TAK-243, or related pathway steps, such as neddylation with pevonedistat, creates a "synthetic lethality" in UBA1-mutated cells by reducing the remaining UBA1 activity to a non-viable level. Consequently, treatment with these substances selectively eradicates UBA1-mutated myeloid progenitor cells, which are the basis of the inflammatory disease and thus holds promise for effectively treating VEXAS patients."

Clinical • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • CD34 • DNMT3A