TAS4464 / Otsuka - LARVOL DELTA

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

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

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

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

Neddylation as a Therapeutic Target in Autoimmune Arthritis: Evidence from SKG Mice (ACR Convergence 2025) - "Upregulated neddylation in inflamed joints could be a novel therapeutic target in autoimmune arthritis."

IO biomarker • Preclinical • Immunology • Inflammatory Arthritis • Rheumatology • Targeted Protein Degradation • CUL1 • NUB1

Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors. (PubMed, Proc Natl Acad Sci U S A) - "Here, we report that pan neddylation inhibitor TAS4464 treatment reversed obesity and adipose inflammation, resulting in improved hepatic steatosis and insulin sensitivity in obese mice...Mechanistically, we found that Cul3 inhibition caused adipose nuclear factor erythroid 2-related factor 2 (NRF2) stabilization, which contributed to impaired adipogenesis by inhibiting lipogenesis. Together, these findings demonstrate that Cul3 is required during adipogenesis and acts as a downstream mediator of the antiobesity effect of pan neddylation inhibitors."

Journal • Diabetes • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • Targeted Protein Degradation

TAS4464, a neddylation inhibitor, mitigates Staphylococcus aureus-induced periprosthetic joint infection by modulating immunosuppressive cell functions. (PubMed, Biomed Pharmacother) - "Furthermore, in a mouse model of PJI, TAS4464 treatment significantly reduced bone destruction and inflammation, which correlates with the inhibition of the neddylation pathway and a decrease in circulating MDSCs and M2 macrophages. These findings suggest that TAS4464 mitigates S. aureus biofilm-associated PJIs by disrupting the immunosuppressive microenvironment and highlight neddylation as a potential therapeutic target."

Journal • Infectious Disease • Inflammation • Targeted Protein Degradation

Functional screens unravelling neddylation as a therapeutic vulnerability in soft tissue sarcoma (ECP 2025) - "More specifically, we have discovered that neddylation inhibitor MLN4924 and TAS4464, but not other protein homeostasis disruptors including proteasome, ubiquitination, heat shock protein and chaperone inhibitors, displayed differential potency towards STS that harbour HRD, possibly by activating Unfolded Protein Response (UPR) induced cell death as previously reported. Our research has discovered neddylation inhibition as a therapeutic vulnerability in STS with HRD, which can potentially stratify patients and improve clinical outcome."

Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Targeted Protein Degradation • HRD

NUB1 reduction promotes PCNA-mediated tumor growth by disturbing the PCNA polyubiquitination/NEDDylation in hepatocellular carcinoma cells. (PubMed, Cell Death Dis) - "Finally, the results of the in vitro and in vivo experiments revealed that the NEDDylation inhibitor TAS4464 could inhibit PCNA NEDDylation to decrease PCNA protein expression, thereby suppressing HCC cell growth...This study provides a new perspective on the specific mechanism of HCC growth. It expands our understanding of the role of NEDDylation in the regulation of substrate proteins and their functions."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • NEDD8 • NUB1 • PCNA

Inhibition of neddylation disturbs zygotic genome activation through histone modification change and leads to early development arrest in mouse embryos. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "In summary, we found that inhibition of neddylation induced epigenetic changes in early embryos and led to abnormalities in related downstream signaling pathways. This study sheds light upon new forms of ubiquitination regulating mammalian embryonic development and may contribute to further investigation of female infertility pathology."

Epigenetic controller • Journal • Preclinical • Gynecology • Infertility • Sexual Disorders • Targeted Protein Degradation • KMT2D • RPL13 • YAP1

Adenosine Sulfamate Analogs inhibit HBV Rna Synthesis and Accelerate The Decay of Viral Transcripts (APASL 2024) - " Both ASAs, MLN4924 and TAS4464, reduced the expression of NAE1, Ubc12, Cul4A and neddylated cullins in PHHs. We demonstrate that ASAs reduce the protein expression of host components of the neddylation pathway, inhibit HBV RNA synthesis and accelerate viral transcript decay. ASAs have potential for future development and repurposing as a novel class of antiHBV therapeutic."

Hepatitis B • CUL4A • NAE1 • UBE2M

Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions. (PubMed, J Hematol Oncol) - "Among them, covalent NAE inhibitors such as MLN4924 and TAS4464 currently entered into clinical trials for cancer therapy, particularly for hematological tumors. In addition, the potential approaches to discover NAE inhibitors and detailed pharmacological mechanisms of NAE inhibitors in the clinical stage are explored in depth. Importantly, we reasonably investigate the challenges of NAE inhibitors for cancer therapy and possible development directions of NAE-targeting drugs in the future."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology

Determinants of GBM vulnerability to inhibitors of NEDD8 Activating Enzyme (NAE) (SNO 2022) - "5 GBM PTENwt models were shown vulnerable to MLN4924 and TAS4464 with average EC50 values 5-10 folds lower than 6 PTENmt/del models. To disclose the relationship between constitutive expression of three gene sets: DNA Replication Fork Progressing, Replication Fork Protection, and Replication Fork Protection Complex, we found that the genes involved in these are significantly under expressed in PTENmt models when comparing to PTENwt models. The molecular determinants of drug response to NAE inhibitors will be further verified in the extended preclinical models and lead to a patient-enrollment "signature of vulnerability" to increase the likelihood of demonstrating therapeutic efficacy in the early stage of clinical trials."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • Targeted Protein Degradation

Nedd8-Activating Enzyme Is a Druggable Host Dependency Factor of Human and Mouse Cytomegalovirus. (PubMed, Viruses) - "Additionally, we raised an MLN4924-resistant cell clone and showed that MLN4924 as well as TAS4464 lose their antiviral activity in these cells. Our results indicate that NAE, the neddylation process, and CRLs are druggable HDFs of cytomegaloviruses."

Journal • Preclinical • Cytomegalovirus Infection • Targeted Protein Degradation

A Dose Finding Study Followed by a Safety and Efficacy Study for Patients With Multiple Myeloma or Lymphoma (clinicaltrials.gov) - P1; N=11; Terminated; Sponsor: Taiho Oncology, Inc.; Phase classification: P1/2 ➔ P1

Clinical • Phase classification • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors. (PubMed, Invest New Drugs) - "Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017."

Clinical • Journal • P1 data • Gastrointestinal Disorder • Oncology • Solid Tumor

TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia. (PubMed, Oncogene) - "TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CASP8 • CASP9 • MYC • PMAIP1

Targeting Cullin-RING E3 Ligases for Radiosensitization: From NEDDylation Inhibition to PROTACs. (PubMed, Front Oncol) - "Over the past decade, research on targeting the cullin-RING (really interesting new gene) E3 ligases (CRLs) in the UPS has gained great momentum with the entry of late-phase clinical trials of its novel inhibitors MLN4924 (pevonedistat) and TAS4464. First-in-class cell-permeable PROTACs against critical radioresistance conferring proteins, including the epidermal growth factor receptor (EGFR), androgen receptor (AR) and estrogen receptor (ER), cyclin-dependent kinases (CDKs), MAP kinase kinase 1 (MEK1), and MEK2, have emerged in the past 5 years. In this review article, we will summarize the most important research findings of targeting CRLs for radiosensitization."

Journal • Review • Oncology • Targeted Protein Degradation • AR • EGFR • ER • MAP2K1 • MAP2K2

TAS4464, a highly potent and selective inhibitor of NEDD8 activating enzyme, suppresses neddylation and shows antitumor activity in diverse cancer models. (PubMed, Mol Cancer Ther) - "TAS4464 showed greater inhibitory effects than those of the known NAE inhibitor MLN4924 both in enzyme assay and in cells. It is, therefore, a promising agent for the treatment of a variety of tumors including both hematologic and solid tumors. These results support the clinical evaluation of TAS4464 in hematologic and solid tumors."

Journal • Preclinical • Oncology • Solid Tumor • Targeted Protein Degradation

Activity of TAS4464, a novel NEDD8 activating enzyme E1 inhibitor, against multiple myeloma via inactivation of NF-κB pathways. (PubMed, Cancer Sci) - "TAS4464 synergistically enhanced the antitumor activities of the standard MM chemotherapies bortezomib, lenalidomide/dexamethasone, daratumumab, and elotuzumab. Together, these results suggest that the anti-MM activity of TAS4464 occurs via inhibition of the NF-κB pathways, and that treatment with TAS4464 is a potential approach for treating MM by single and combination therapies."

Journal