pevonedistat (MLN4924) / Takeda - LARVOL DELTA

Non-Canonical Neddylation of TGFBR2 as a Therapeutic Target in BRAF-Mutant Melanoma (AAD 2026) - " GSEA data indicated that MLN4924 treatment significantly suppressed key oncogenic pathways, including TGF-β signaling and epithelial-mesenchymal transition (EMT). Functionally, TGFBR2 knockdown reduced migration and immunosuppressive abilities in highly metastatic cell lines, while its overexpression promoted these malignant phenotypes and increased resistance to the BRAF inhibitor PLX4720... Our findings demonstrate that the non-canonical neddylation of TGFBR2 is a critical mechanism driving therapeutic resistance, metastasis, and immunosuppression in BRAF V600E melanoma. Targeting this specific neddylation-TGFBR2 axis offers a promising novel strategy to improve treatment outcomes."

Melanoma • Solid Tumor • BRAF • TGFBR2

Defining the role of nucleolar stress in mediating DDB2 induced oxaliplatin resistance in colorectal cancer (AACR 2026) - "Oxaliplatin containing regimens are generally considered first line therapy for fit patients, either in the form of FOLFIRINOX or NALIRIFOX. However, acquired resistance is inevitable and a significant percentage of patients treated with adjuvant FOLFOX (5-FU/leucovorin/oxaliplatin) fail to respond...We and others have shown that oxaliplatin, but not cisplatin resistance in tumor cells is dependent upon the levels of DDB2, a DNA repair protein involved in damage recognition in chromatin during global genome nucleotide excision repair (GG-NER)... Our studies demonstrate that DDB2 is a potential biomarker for response to oxaliplatin and a new clinically targetable protein in the treatment of CRC. These studies will lay the foundation for clinical trials of combination therapy of Pevonedistat or CSN5i with oxaliplatin and 5FU."

Colorectal Cancer • Oncology • Solid Tumor • DDB2 • NPM1

Targeting the Glutamine Transporter SLC1A5 Enhances Sensitivity of Acute Myeloid Leukemia to MLN4924. (PubMed, Biomedicines) - "Co-targeting neddylation and glutamine transporter SLC1A5 synergistically exerts anti-leukemic effects, at least in part through disruption of the TCA cycle. This combination represents a novel and effective therapeutic strategy against AML."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CD14 • ITGAM • SLC1A5

Targeting the non-canonical neddylation of TGRBR2 suppresses the metastatic potentials of oral squamous cell carcinoma (AACR 2026) - "Cetuximab, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), in combination with radiotherapy, has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of recurrent or metastatic OSCC...Therefore, elucidating the crosstalk between TGF-β receptor signaling and EGFR-mediated signal transduction may be critical for the future precision management of OSCC. Gene set enrichment analysis (GSEA) was applied to predict the potential mechanisms through which the protein neddylation inhibitor MLN4924 (Pevonedistat) suppresses cellular migration and lymph node metastasis in OSCC... This study is the first to demonstrate that non-canonical c-Cbl-mediated neddylation of TGFBR2 plays a decisive role in driving OSCC metastatic progression."

Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • TGFB1 • TGFBR2

Characterizing neddylation as a potential vulnerability in MYC-amplified medulloblastoma (AACR 2026) - "We hypothesize that characterizing neddylation in MYC-amplified MB will identify novel therapeutic vulnerabilities, and that targeting neddylation is a rational therapeutic strategy for MYC-amplified MB. Cell viability assay was conducted in four MYC-amplified MB cell lines and normal human astrocyte (NHA) control after 96hr treatment of neddylation inhibitor MLN4924 or TAS4464. These findings establish neddylation as a critical dependency in MYC-amplified MB, essential for maintaining MYC protein stability and tumor cell survival. The potency of TAS4464 provides preclinical validation for targeting neddylation pathway. Our proteomics data unveiled a previously unrecognized dimension of neddylation in MB, identifying mRNA splicing machinery as a targetable vulnerability."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • MYC

The ubiquitin E3 ligase SCFSkk2/Cks1complex: A critical node coupling cell cycle control, tumorigenesis, and lineage fidelity in small cell lung cancer (SCLC) (AACR 2026) - "Cell lines derived from the RPPt lung tumors grew more rapidly and were more sensitive to cisplatin and etoposide than were the lung tumor cells from the RPPt-Cks1N45R KI mice. The RPPt lung tumor cells were also more sensitive to growth inhibition by the SCFSkp2/Cks1 inhibitors C1 and pevonedistat and the CDK1/2/5/9 inhibitor dinaciclib... These findings are consistent with the hypothesis that the Rb1/Trp53-deficient SCLC neuroendocrine phenotype is not a fixed feature but can vary with the presence of other oncogenic drivers, and document SCFSkp2/Cks1 as one such driver. This could reflect an early, deterministic lineage redirection toward a YAP1-high, SMARCA4-intact, non-neuroendocrine phenotype. SCFSkp2/Cks1 mediates lung cancer heterogeneity, plasticity and sensitivity to standard cytotoxic and targeted drugs."

Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • CDK1 • KRT5 • PTEN • RB1 • SKP2 • SMARCA4 • SOX2 • TP63 • YAP1

Natural product PROTACylation: Development of Maslinic acid-based JAK2 degraders for cancer therapy. (PubMed, Fitoterapia) - "Competitive inhibition experiments using excess MA or lenalidomide, along with MLN4924 treatment, validated the requirement for ternary complex formation and cullin-RING E3 ligase pathway dependence. P4 effectively downregulates the IL-6/JAK2/STAT3 signaling axis and simultaneously activates dual apoptotic pathways: intrinsic mitochondrial apoptosis (decreased Bcl-2, XIAP, survivin; increased Bax, cytochrome c, cleaved caspases) and ER stress-mediated apoptosis (elevated IRE1, BIP, ATF4, CHOP, p-JNK1, cleaved caspase-12). This work establishes P4 as a promising JAK2-targeting degrader whose anticancer efficacy derives from coordinated target elimination, oncogenic pathway suppression, and dual apoptotic pathway activation, validating natural product PROTACylation as a viable strategy for developing multifunctional anticancer therapeutics."

Journal • Oncology • Targeted Protein Degradation • ATF4 • BCL2 • BIRC5 • CASP12 • CRBN • ERN1 • IL6 • JAK2 • MAPK8 • XIAP

IDENTIFICATION OF NEURONAL SUBTYPE-SPECIFIC SPLICE VARIANTS IN IPSC-DERIVED CELL MODELS OF ALS AND FTD (ADPD 2026) - "Our data demonstrates that our iPSC-derived ALS/FTD cell models provide a platform to delineate TDP-43 function and identify cell specific target transcripts of TDP-43, and are valuable tools to study ALS/FTD and screen for drugs that can modulate the progression of these devastating diseases."

Amyotrophic Lateral Sclerosis • CNS Disorders • SETD5 • TARDBP

IMPROVED ALZHEIMER'S DISEASE MODEL WITH A HUMAN-IPSC-DERIVED TRI-CULTURE SYSTEM FOR DRUG SCREENING (ADPD 2026) - "These findings support that our model recapitulates AD hallmarks and thus stands as a physiologically competent platform for high-throughput drug screening."

Alzheimer's Disease • CNS Disorders • GFAP • GLB1 • MMP3 • MT-CO2 • UBA3

Viral subversion of neddylation: dual roles in replication efficiency and evasion of antiviral immunity. (PubMed, Arch Virol) - No abstract available

Journal • Review

Νοvel Therapies in High-Risk Myelodysplastic Syndromes. (PubMed, Eur J Haematol) - "Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies."

Journal • Review • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • HAVCR2 • IDH1 • IDH2

Few Drug Approvals in MDS: Lessons and Insights from a Decade of Clinical Trials (ICKSH 2026) - "Aside from allogeneic transplantation, the current standard of care approach for higher -risk myelodysplastic syndromes/neoplasms (HR -MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazurid ine...In this lecture , I will discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR -246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, I will advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, I will emphasize the need for the scientific community to access patient -level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials."

Clinical • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • TP53

Integrative In Silico Multi-Omics Profiling of circRNA-Mediated ceRNA Networks Reveals Prognostic Biomarkers and Repurposed Therapeutic Candidates in Gastric Cancer. (PubMed, Int J Mol Sci) - "To explore therapeutic implications, transcriptomics-guided drug repositioning combined with molecular docking analysis identified five candidate compounds-celastrol, fedratinib, pevonedistat, tozasertib, and withaferin A-predicted to target key network hubs. Overall, this in silico study provides a ceRNA-centered regulatory framework for GC and prioritizes biologically informed biomarkers and repositioned drug candidates with potential applicability across other malignancies to converge precision oncology."

Biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Oncology • Solid Tumor • COL4A1 • IGF2BP3 • MMP14 • TGM2

Functional screens to uncover neddylation as a therapeutic vulnerability in sarcoma (Sarcoma-RC 2026) - "Inhibition of the NEDD8-activating enzyme (NAE) with pevonedistat triggered the activation of the unfolded protein response (UPR) pathway and ultimately apoptosis specifically in cell models with HRD...Legal entity responsible for the study University of Zurich. Funding Sassella foundation; Innovation Pool from University Hospital Zurich."

Osteosarcoma • Sarcoma • Solid Tumor • HRD

Regulation of Cellular Signaling by CUL5 is Dependent on Its Neddylation Status. (PubMed, Cell Physiol Biochem) - "These findings suggest that modification of CUL5 by NEDD8 may occur at multiple lysine residues and that multi-site neddylation may contribute to the diverse regulatory effects of CUL5 on cellular signaling and proliferation."

Journal • Oncology • Targeted Protein Degradation • ER

Integrated bioinformatics analysis and experimental validation reveal Pevonedistat as a promising therapeutic agent modulating the CRL4-DTL-p21/p53 axis in nasopharyngeal carcinoma. (PubMed, Hereditas) - No abstract available

Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • CDKN1A • IL17RB

Single-cell transcriptomic signatures identify drug combinations to address platinum resistance in ovarian cancer (ESGO 2026) - "Among 64 predicted drugs, the NEDD8-activiating enzyme (NAE) inhibitor pevonedistat, the inhibitor of apoptosis (IAP) inhibitor LCL161 and the bromodomain (BRD2/3/4) inhibitor birabresib, exhibited a long-term inhibitory effect in two organoid models. Even though this combination treatment did not result in significant survival benefit, it reduced the tumour size, metastatic dissemination and staging of the disease. Conclusion We demonstrate that targeting transcriptional resistance signatures with selective inhibitors can partially reverse carboplatin resistance in clinically relevant organoid and PDX models, supporting their potential as combination strategies to improve therapeutic response."

Oncology • Ovarian Cancer • Solid Tumor • BRD2

The Degradation Pathway of COP9 Signalosome-Cullin-RING Ubiquitin Ligase Complexes via Autophagy. (PubMed, Biomolecules) - "Selective macroautophagy can be blocked by chloroquine, a specific inhibitor of autophagy. Interestingly, the process can also be inhibited by MLN4924, a neddylation inhibitor...Confocal fluorescence microscopy produces images that suggest the localization of CSN-CRL particles in autophagosomes. Our data place CSN-CRL in the category of large complexes that are degraded through autophagy."

Journal • Targeted Protein Degradation

Pevonedistat targeting NEDDylation activating enzyme for human diseases: Underlying mechanisms, clinical studies, and future directions. (PubMed, Pharmacol Res) - "Review offers new perspectives for the future research on pevonedistat. By a systematic understanding of relevant findings, this review highlights the immense potential of pevonedistat for human diseases and facilitates the promotion of targeting NEDDylation as a new and effective therapeutic strategy."

Journal • Review • CNS Disorders • Heart Failure • Immunology • Infectious Disease • Metabolic Disorders • Oncology • Targeted Protein Degradation

SIRT1 reduced DDX5 neddylation to attenuate myocardial ischemia/reperfusion injury. (PubMed, Hum Cell) - "These results suggested that SIRT1 increased DDX5 protein level to reduce cardiomyocytes apoptosis and ROS level via the inhibition of DDX5 neddylation, thus alleviating MI/RI."

Journal • Cardiovascular • Myocardial Ischemia • Reperfusion Injury • DDX5 • SIRT1

A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons. (PubMed, bioRxiv) - "Using this sensor, we screened a small collection of small-molecule modulators of proteostasis network function and identified Neddylation inhibition by Pevonedistat as a robust promoter of soluble tau degradation. Mechanistic analysis including proteomic profiling revealed that Neddylation inhibition hastens HaloTag-Tau clearance via compensatory activation of a proteasome-dependent pathway(s) as well as the autophagy-lysosome pathway. Our findings establish a powerful tool for probing tau homeostasis and highlight Neddylation inhibition as a potential therapeutic approach for enhancing both proteasome and lysosome-mediated tau clearance in tauopathies."

Journal • CNS Disorders

Interstitial cystitis-related gene CCDC8 accelerates tumorigenesis by participating in CUL7-mediated degradation of P53 in bladder cancer. (PubMed, Oncogene) - "Pharmacological inhibition of neddylation with MLN4924 restored P53 levels and reversed the oncogenic effects of CCDC8 both in vitro and in vivo. Together, these findings highlight a novel mechanism of P53 regulation in bladder cancer, position CCDC8 as a potential biomarker and therapeutic target, and suggest a molecular link between chronic bladder inflammation and malignant transformation."

Journal • Bladder Cancer • Genito-urinary Cancer • Interstitial Cystitis • Oncology • Solid Tumor • Targeted Protein Degradation • CDKN1A • CUL7

DCUN1D5 promotes the proliferation and migration of colorectal cancer tumors in vitro and in vivo. (PubMed, Cancer Cell Int) - "DCUN1D5 contributes to the growth and motility of CRC in vitro and in vivo."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor • CUL1

Progression on Mechanism and Therapeutic Implications of Neddylation in Lung Cancer. (PubMed, Oncol Res) - "Meanwhile, it concludes the current advances in potential therapeutic agents targeting neddylation-related targets, including small-molecule compounds (such as Pevonedistat) and natural extracts (such as arctigenin). Finally, the review prospectively evaluates the application potential and questions requiring further exploration of neddylation in lung cancer treatment. In conclusion, we aim to systematically summarize the biological process of neddylation, critically explore its roles in lung cancer proliferation, metastasis, and drug resistance, and evaluate the therapeutic potential of neddylation-targeting agents."

Journal • Review • Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

The NEDD8-activating enzyme inhibitor MLN4924 reduces inflammation, blood-brain barrier disruption and brain injury after intracerebral hemorrhage in mice. (PubMed, J Neuroimmunol) - "Inhibiting ERK5 reversed the beneficial effects of MLN4924 on inflammation, BBB disruption, and neurobehavioral deficits. Collectively, inhibition of the NEDD8 pathway by MLN4924 attenuates inflammation, BBB disruption, and neurological deficits via the p-ERK5-KLF2-ICAM-1 axis, highlighting NEDD8 pathway as a potential therapeutic target for ICH."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Inflammation • Oncology • Targeted Protein Degradation • Vascular Neurology • CUL1 • ICAM1 • NEDD8