subasumstat (TAK-981) / Takeda - LARVOL DELTA

Selective targeting of sumoylation disrupts mitochondrial homeostasis via TRAP1 to suppress growth of non-Hodgkin lymphoma (NHL) B-cells (ASH 2025) - "TAK981 disrupts mitochondrial sumoylation, resulting in metabolic dysfunction andapoptosis in B-NHL cells. These findings identify sumoylation and TRAP1 regulation as a potentialtherapeutic vulnerability in lymphoma."

B Cell Lymphoma • Hematological Malignancies • Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Targeted Protein Degradation • MYC • PKM

A Study of TAK-981 Given With Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=161 | Completed | Sponsor: Takeda | N=109 ➔ 161

Enrollment change • Cervical Cancer • Colorectal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • NTRK • ROS1

Immunomodulation of Pancreatic Cancer via Inhibition of SUMOylation and CD155/TIGIT Pathway. (PubMed, Mol Cancer Ther) - "Previous studies have shown that inhibition of the E1 enzyme, which catalyzes the small ubiquitin-like modifiers (SUMO), with the small molecule TAK-981, can reprogram the TME to enhance immune activation and suppress tumor growth...Mechanistic studies suggest that SUMO E1 inhibition enhances antibody-mediated elimination of Tregs through innate immune cells, potentially by activation of type I interferon responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy."

Journal • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • CD4 • FOXP3 • PVR • TIGIT

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

Targeting Sumoylation Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment (ASH 2023) - "Acute myeloid leukemia (AML) is a hematopoietic cancer characterized by aberrant immature myeloid progenitor blasts in bone marrow and peripheral blood. More importantly, TAK-981 showed remarkable therapeutic effect in patient-derived xenograft (PDX) mouse model engrafted with blasts isolated from R/R AML patients, and significantly synergized with VEN at extending mice survival in vivo. In conclusion, TAK-981 enhances the antileukemic activity of VEN by targeting mitochondria function and metabolism, offering a potent therapy for refractory/relapsed AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ANXA5 • CASP3

Inhibition of Topors Ubiquitin Ligase Augments the Efficacy of DNA Hypomethylating Agents through DNMT1 Stabilization (ASH 2023) - "MDS-L and MOLM-13 cells expressing Cas9 were infected with an sgRNA lentiviral library containing 12,409 sgRNAs targeting 1,383 epigenetic factors and exposed to low-dose HMAs, decitabine (DAC) or azacitidine (AZA), for 14 days...Furthermore, an ubiquitination inhibitor TAK-243 as well as a SUMOylation inhibitor TAK-981 showed synergistic effect with HMAs through DNMT1 stabilization. These results suggested that they are likely to be promising therapeutic agents in clinical practice. Our findings unveil a novel mechanism of resistance to HMAs and provide an attractive therapeutic strategy for myeloid malignancies that interferes with resolution of DNA-DNMT1 crosslinks by targeting DNMT1 post-translational modification."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • DNMT1 • UHRF1

Electroacupuncture-Induced SUMOylation and ACE2 Replacement: Dual Approaches to Mitigate AKI Inflammation (KIDNEY WEEK 2025) - "Some animals received a SUMOylation inhibitor (TAK-981) or underwent splenectomy...ACE2 shedding in ischemic AKI contributes to DGF pathogenesis, and ACE2 supplementation via machine perfusion improves renal recovery. These findings highlight two distinct, targetable pathways—SUMOylation and ACE2 signaling—for modulating innate immunity and improving kidney transplant outcomes."

Acute Kidney Injury • Cardiovascular • Infectious Disease • Inflammation • Nephrology • Reperfusion Injury • Septic Shock • TNFA

TRIM28 Facilitates Chronic Myeloid Leukemia Progression By Enhancing Sumoylation and Stability of BCR-ABL (ASH 2024) - "To explore the function of SUMOylation in CML, we treated CML cells with SUMOylation inhibitors, 2-D08 and TAK-981...BCR-ABL degradation induced by TRIM28 knockdown or knockout was reversed by autophagy-lysosome inhibitor, chloroquine, and 3-methyladenine (3-MA), but not by the proteasome inhibitor MG132...To investigate whether TRIM28 inhibited BCR-ABL protein level to overcome TKI resistance, we used the imatinib-resistant cell line, K562/G01...In conclusion, we demonstrate that upregulated TRIM28 facilitated the SUMOylation of BCR-ABL and subsequently inhibited p62-mediated autophagic degradation, resulting in the progression of CML. Our findings reveal a novel PTM regulating BCR-ABL protein expression and a new therapeutic method for CML."

Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ABL1 • BCR • SUMO3 • TRIM28

DNMT3A Stability Is Maintained By Ubiquitin-Specific Peptidase 11 (USP11) and Sumoylation Countering Degradation (ASH 2024) - "Furthermore, we treated Kelly and THP-1 cells with TAK-981, an inhibitor of the SUMO activating enzyme; TAK-981 induced DNMT3A1 destabilization...In summary, the deubiquitinating enzyme USP11 SUMOylates DNMT3A1 and maintains steady-state protein levels, counteracting the activity of DCAF8. Using our molecular findings, we will pursue the development of therapeutic strategies to modulate DNMT3A to impact CH and hematologic malignancies."

Hematological Malignancies • Neuroblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • DNMT3A • PIAS4 • USP1 • USP11 • USP41 • USP7

Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma. (PubMed, Nat Commun) - "TAK-981 synergizes with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability."

Journal • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • SS18

A First-In-Human Study of the SUMOylation Inhibitor Subasumstat In Patients With Advanced/Metastatic Solid Tumors or Relapsed/Refractory Hematologic Malignancies. (PubMed, Cancer Res Commun) - P1/2 | "Subasumstat had a manageable safety profile, with evidence of innate and adaptive immune response engagement in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Further studies are needed to determine the role of subasumstat in cancer treatment."

First-in-human • Journal • P1 data • CNS Disorders • Cognitive Disorders • Dental Disorders • Developmental Disorders • Fatigue • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Pneumonia • Solid Tumor • Stomatitis

SUMOylation of DYRK1B facilitates gastric cancer metastasis by phosphorylating SFPQ (ESSO 2025) - "Furthermore, combined treatment with the DYRK1B inhibitor AZ191 and SUMOylation inhibitor TAK-981 significantly inhibited GC metastasis in mouse models.Conclusions (For surgical proposals, write down NA) CBX4/SENP1-regulated SUMOylation of DYRK1B enhances its kinase activity, which subsequently promotes GC invasion and metastasis by phosphorylating SFPQ and inducing its phase separation, thereby reprogramming global alternative splicing in GC cells. These findings provide novel molecular targets and highlight the clinical potential for therapeutic intervention in GC metastasis."

Gastric Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • DYRK1B

Unraveling the critical role of SUMOylation in the governing of tumor immunity. (PubMed, Front Immunol) - "As current phase I trials suggest dose-dependent toxicity of TAK-981, there is a need for targeted delivery systems; AI-assisted screening of novel SUMOylation inhibitors (SUMOi) which are FDA approved serves as another potential approach; besides, antibodies against these pivotal SUMOylated molecules in tumors could be conjugated with SUMOi to restore the activity of specific proteins in tumor microenvironment. In all, our review proposes that current or other novel strategies for SUMOylation inhibition stands as a promising adjuvant to immunotherapy for tumor management, thereby potentially contributing to the favorable prognosis of cancer patients."

Journal • Review • Head and Neck Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Targeted Protein Degradation

SUMOylation and an ATS1 variant converge to disrupt PIP2-dependent gating of Kir2.1. (PubMed, J Gen Physiol) - "Inhibiting the SUMO pathway with TAK-981 prevents this suppression and enhances current in both WT and R67Q-containing channels...These findings support a two-hit model of channel dysfunction, in which a genetic variant and an environmental stressor act through a common structural mechanism to impair Kir2.1 gating. By identifying PIP2 destabilization as the point of convergence, this work provides new insight into how stress-sensitive channelopathies arise and suggests that SUMO pathway inhibition may offer a strategy to restore function under adverse physiological conditions."

Journal • Cardiovascular

Synergism of SUMOylation Inhibition with Irinotecan for the Treatment of Pancreatic Cancer Free (AACRPanCa 2025) - "We investigate a new strategy of combining IRI with sumoylation inhibition (SUMOi, Subasumstat [SST])...In Vitro Synergy: KPC46 murine PDAC (KPMP) cells and human PDAC organoids were treated with 5-FU, Irinotecan, Oxaliplatin, Gemcitabine, or Cisplatin and SST (1nM- 500nM, 24hrs), viability was assessed with cell titer glo, and synergy plots were generated using Combenefit.Survival Experiments: NSG and F1 hybrid (F1H) mice underwent orthotopic KPC46 cell injection; IP injections with SST (15mg/kg q48h) and/or IRI (F1H:25mg/kg, NSG:12.5mg/kg) qweekly were initiated when tumors reached 3-5mm...SST+IRI exhibits synergistic cytotoxicity on PDAC cells in both murine and human models by enhancing cancer cell apoptosis due to increased Top1 binding and dsDNA breaks. Clinically, addition of SST could serve as an adjunct to FOLFIRINOX and SST+IRI can be an alternative second line treatment to FOLFIRI."

Oncology • Pancreatic Cancer • Solid Tumor • CASP3 • TOP1

From sterility to selectivity: a C. elegans synthetic lethality screen reveals non-conserved vulnerabilities in ATRX-deficient glioma (EANO 2025) - "Corresponding small-molecule inhibitors—TAK-981 (SUMO pathway), UNC-0642 (H3K9 methylation), and G007-LK (tankyrase inhibition)—were evaluated in ATRX-deficient HeLa-LT and SF188 cell lines. Cell viability was measured under single-agent and combination treatments with DNA-damaging agents (doxorubicin, bleomycin). RNAi of top hits, including gei-17 and set-25, induced significant fertility defects in xnp-1 mutants...Although the candidate compounds identified through C. elegans synthetic sterility screens did not produce selective cytotoxicity in ATRX-deficient human cancer cells, this outcome provides valuable insight into the translational landscape of cross-species screening. The fertility-based phenotype in xnp-1 mutants likely captures gene interactions relevant to germline development and stress responses, which may not be conserved in cancer biology. By reporting these results, we aim to contribute to a more informed and efficient use of model organisms in..."

Synthetic lethality • Brain Cancer • Glioma • Oncology • Solid Tumor • ATRX

TAK-981 potentiates doxorubicin immunocide in triple-negative breast cancer by IFN I-dependent NK cell stimulation. (PubMed, Cell Oncol (Dordr)) - "The combination of an immunomodulatory agent with chemotherapy represents a novel therapeutic strategy for TNBC. TAK-981 not only synergizes with DOX to produce antitumor immun effects but also significantly mitigates DOX-induced cardiotoxicity, offering a promising new direction for improving the efficacy and safety of TNBC treatment."

Journal • Breast Cancer • Cardiovascular • Fibrosis • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer • JAK1 • NKG2D • STAT1 • ULBP2

SUMOylation Inhibition by TAK-981 Enhances Targeted Therapy and Immune Modulation in AML (ICBMT 2025) - "Our findings support SUMOylation as a therapeutic target in AML and demonstrate that TAK-981 has synergistic anti-leukemic effects with venetoclax or gilteritinib, along with immune-modulating activity in immunocompetent models, highlighting its potential for future combination strategies. Keywords: AML, SUMOylation, TAK-981, Immunomodulation, Drug Synergy"

Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Immunology • Leukemia • ANXA5 • CD8 • SAE1 • UBE2I

Peripheral Blood Mononuclear Cell Gene Expression Signatures Predict Long-term Survivorship in Canine DLBCL. (PubMed, Res Sq) - "We recently completed a clinical trial in dogs with DLBCL using a combination of canine anti-CD20 antibody and low dose doxorubicin followed by one of three small molecule immune-modulating agents (KPT-9274, TAK-981 or RV1001). To facilitate point-of-care PBMC gene expression testing that could be used to distinguish those dogs likely to require more intensive treatment regimens in advance of relapse, we developed qPCR assays for TBHD, NPNT and ISG20 . Together these data provide proof of principle that biomarker interrogation in PBMCs can help predict early relapse and poor responders to inform clinical management of DLBCL."

IO biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • DDX58 • MYC

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis. (PubMed, EMBO J) - "TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability...Further, genetic depletion or SUMO2 inhibition reduced global expression levels and chromatin occupancy of the SS18::SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark facilitating SySa pathogenesis. Taken together, our study identifies SUMO2 as a novel, selective vulnerability in synovial sarcoma, suggesting new avenues for targeted treatment of soft tissue tumors."

Journal • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • Targeted Protein Degradation • SS18

SUMOylation Regulates Neutrophil Phagocytosis and Migration. (PubMed, Pharmaceuticals (Basel)) - "SUMOylation was inhibited with TAK-981, and its impact on neutrophil migration, NETosis, and phagocytosis was assessed in vitro... Our work identifies SUMOylation as a novel mechanism of neutrophil tissue reprogramming. Blocking SUMOylation may provide a therapeutic option to limit the contribution of neutrophils to inflammation-associated tissue damage."

Journal • Cardiovascular • Inflammation • Targeted Protein Degradation

Targeting SUMOylation triggers interferon-ß-dependent activation of patient and allogenic Natural Killer cells in preclinical models of Acute Myeloid Leukemia. (PubMed, Mol Cancer Ther) - "Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cells degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, FasL) and cytotoxicity against AML cells...Surprisingly, IFNB1 induction does not require its best-characterized activators MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical IFN-I pathway, which enhances the anti-leukemic potential of NK cells."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Transplantation • FASLG • IFIH1 • IFNG • IRF1 • TNFA

SUMOylation is not a prerequisite for HSF1's role in stress protection and transactivation. (PubMed, Sci Rep) - "SUMOylation inhibition using Subasumstat also led to altered nuclear stress bodies morphology but did not impair Hsp70 induction or enhance Hsp90 inhibitor cytotoxicity. Our findings reveal that SUMOylation is dispensable for HSF1 activation and transactivation capacity during the early phase of HSR. These results refine our understanding of HSF1 regulation and suggest that alternative strategies targeting HSF1 stability and degradation may enhance the therapeutic efficacy of proteostasis-targeting cancer therapies."

Journal • Lung Cancer • Oncology • Solid Tumor • CDC37 • HSF1

Synthetic inhibition of the SUMO pathway by targeting the SAE1 component via TAK-981 compound impairs growth and chemosensitizes embryonal and alveolar rhabdomyosarcoma cell lines. (PubMed, Mol Cell Biochem) - "Its activity was effectively counteracted by TAK-981, a SUMO inhibitor that demonstrated significant therapeutic potential by suppressing RMS cell proliferation and migration, and enhancing the cytotoxic effects of chemotherapeutic agents actinomycin D and doxorubicin. The findings of this study establish TAK-981 as a promising therapeutic agent for RMS. The results also provide foundational insights into the role of SUMOylation associated with the new biomarker SAE1 in RMS and its subtypes, paving the way for the development of personalized treatment strategies that leverage SUMO pathway inhibition."

Journal • Preclinical • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CAV1 • SAE1

Quantitation of TAK-981 in human plasma via LC-MS/MS and its application in clinical trials. (PubMed, Bioanalysis) - "This assay was successfully validated from 0.1 ng/mL to 100 ng/mL with good accuracy and precision and has been applied to support clinical studies. A sensitive and robust LC-MS/MS assay was validated for TAK-981 in human plasma for the first time."

Journal • Oncology • Targeted Protein Degradation