subasumstat (TAK-981) / Takeda - LARVOL DELTA

A novel long-term TMZ resistance mouse model reveals SUMOylation as a targetable driver of DNA repair in glioblastoma (EANO 2026) - "Although temozolomide (TMZ) is the standard chemotherapy for GBM, resistance almost invariably develops. We developed a novel long-term TMZ resistance mouse model that recapitulates acquired chemoresistance in glioblastoma in vivo. Using this model, we identify SUMOylation as a potential driver of enhanced DNA repair and TMZ resistance, highlighting SUMO pathway inhibition as a promising therapeutic strategy in GBM."

Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • RAD50

Phase I/II Study of Subasumstat (TAK-981) in Combination With Rituximab in Relapsed/Refractory Non-Hodgkin Lymphoma. (PubMed, Clin Lymphoma Myeloma Leuk) - "This study demonstrated a positive benefit-risk profile of subasumstat combined with rituximab in NHL."

Journal • P1/2 data • Fatigue • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A phase 1b, multicenter, dose-escalation study of subasumstat (TAK-981) in combination with pembrolizumab in patients (pts) with advanced solid tumors. (ASCO 2022) - P1b/2 | "Subasumstat plus pembrolizumab showed a favorable safety profile and promising anti-tumor activity in pre-treated NSCLC and MSS-CRC pts. Updated data will be presented at the meeting. Subasumstat plus pembrolizumab is currently in phase 2 clinical development (NCT04381650)."

Clinical • Combination therapy • P1 data • Anemia • Cardiovascular • Colorectal Cancer • Dental Disorders • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Stomatitis • CD8

Pharmacological inhibition of the SUMOylation pathway: mechanisms, inhibitors and therapeutic opportunities. (PubMed, Pharmacol Res) - "Their mechanisms of action, biochemical potency, structural validation, cellular target engagement, in vivo efficacy, PK/PD properties, and developmental status are critically evaluated. Overall, this review provides a comprehensive pharmacological framework for understanding SUMO pathway inhibition and highlights key considerations for the development of next-generation SUMO-directed therapeutics."

Journal • Review • CNS Disorders • Immunology • Oncology • Targeted Protein Degradation • UBE2I

SUMOylation modulates glucocorticoid-induced muscle toxicity in cell and mouse models. (PubMed, Sci Rep) - "Pharmacological modulation of SUMOylation was examined using the SUMOylation activator N106 in differentiated C2C12 myotubes and in a DEX-treated mouse model, both subjected to dexamethasone (DEX) treatment. Morphological, transcriptional, and functional parameters were assessed in vitro and in vivo, and the requirement for SUMO conjugation was interrogated using the SUMO E1 inhibitor TAK981...Collectively, these findings identify SUMOylation as a post-translational regulatory layer that constrains GR-mediated catabolic transcription under GC stress. Chemical modulation of the SUMOylation pathway influences the severity of GC-induced muscle atrophy, highlighting SUMOylation as an important determinant of skeletal muscle susceptibility to GC-induced toxicity."

Journal • Preclinical • Muscular Atrophy • FBXO32 • KLF5 • PDK4

SUMOylation inhibitor TAK-981 suppresses proliferation and induces apoptosis in SK-UT-1B uterine leiomyosarcoma cells. (PubMed, Oncol Lett) - "By contrast, autophagy markers, such as LC3B and p62, were unchanged, indicating that TAK-981 exerted its cytotoxic effects independently of the autophagic pathway. Collectively, these findings suggested that TAK-981 suppressed proliferation and induced apoptosis in SK-UT-1B Ut-LMS cells, accompanied by SUMOylation inhibition, ROS-associated mitochondrial dysfunction, apoptosis and G0/G1 cell-cycle arrest, and may represent a promising therapeutic candidate for further investigation in Ut-LMS."

Journal • Leiomyosarcoma • Metabolic Disorders • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation • Uterine Leiomyosarcoma • ANXA5 • CASP3 • CDKN1A

Inhibition of the SUMOylation pathway augments factor VIII expression following AAV-based gene delivery for hemophilia A (ISTH 2026) - "In studies of an inhibitor of SUMOylation, TAK-981, we observed that treatment with TAK- 981 at the time of AAV administration or long after delivery of an AAV vector expressing a luciferase reporter in mice (AAV8-CMV-luciferase), transiently boosted transgene expression up to 100-fold...Further studies investigating the mechanism by which SUMOylation modulates AAV transduction and transcription may inform new strategies for improving transgene expression, enabling lower vector doses in AAV gene therapy. DOI*10.1016/j.rpth.2026.103752"

Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

The role of SUMOylation in regulating proteins that drive neuronal disease progression. (PubMed, Biochem Biophys Rep) - "From a therapeutic standpoint, the SUMO inhibitor TAK-981 has shown promise in both Multiple Sclerosis and in pre-clinical glioblastoma models, underscoring the translational potential of targeting of this pathway. This review examines the multifaceted role of SUMOylation across diverse neurological conditions, evaluates the therapeutic potential of SUMO inhibitors and activators, and highlights the opportunities and challenges of modulating this pathway in currently incurable neurological disorders."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • Brain Cancer • Cardiovascular • CNS Disorders • Glioblastoma • Huntington's Disease • Movement Disorders • Multiple Sclerosis • Oncology • Parkinson's Disease • Progressive Supranuclear Palsy • Solid Tumor • Targeted Protein Degradation

A Study of TAK-981 Given With Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1b/2 | N=265 | Recruiting | Sponsor: Takeda | Trial completion date: Sep 2023 ➔ Nov 2025 | Trial primary completion date: Sep 2023 ➔ Nov 2025

Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Melanoma • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • EGFR • MSI • NTRK • ROS1

A Study of TAK-981 Given With Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=231 | Recruiting | Sponsor: Takeda | Phase classification: P1b/2 ➔ P1/2

Metastases • Phase classification • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • NTRK • ROS1

SUMOylation of HMGCS1 triggers its ubiquitin-dependent degradation to alleviate hepatic steatosis. (PubMed, Metabolism) - "Our study establishes global hepatic SUMOylation as a druggable regulatory node in MASLD and delineates a SUMO-ubiquitin pathway centered on HMGCS1. Pharmacological activation of this axis via N106 represents a promising preclinical therapeutic strategy, highlighting the potential of targeting the SUMOylation machinery in metabolic liver disease."

Journal • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Targeted Protein Degradation • HMGCS1 • RANBP2 • UBE2I

Therapeutic targeting of oxygen sensing and SUMO protein modification pathways in renal cell carcinoma (RCC) (EACR 2026) - "Our results suggest that i) there is a functional crosstalk between SUMOylation and O2-sensing pathways in RCC and that ii) inhibition of global SUMOylation may have therapeutic potential in RCC."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • HIF1A

SUMOylation-driven nuclear translocation of HSF2BP alleviates MASLD via COX6A1-dependent mitochondrial reprogramming. (PubMed, Cell Death Dis) - "Pharmacological inhibition of SUMOylation using TAK-981 abolishes the protective effect of HSF2BP against hepatic steatosis, whereas enhancing SUMOylation through UBC9 overexpression or treatment with the SUMO activator N106 markedly ameliorates lipid accumulation in the liver. Collectively, our findings uncover a SUMOylation-dependent mechanism by which HSF2BP regulates mitochondrial integrity and lipid homeostasis, providing a promising therapeutic axis for MASLD."

Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • UBE2I

SUMOylation in cancer: molecular mechanisms and therapeutic implications. (PubMed, Mol Cancer) - "Pharmacological inhibition of SUMOylation (e.g., TAK-981, ML792) reverses these immunosuppressive effects by restoring antigen presentation, activating type I interferon responses, enhancing CD8 + T cell cytotoxicity, and reducing regulatory T cells...Furthermore, preclinical models demonstrate that SUMOylation inhibitors synergize with immune checkpoint blockade to enhance anti-tumor efficacy, although this synergistic effect has not yet been validated in clinical settings. This review consolidates current knowledge on the immunologic and translational dimensions of SUMOylation-from molecular mechanisms to therapeutic implications-into a single narrative focused on how SUMOylation shapes the TIME and its implications for cancer immunotherapy."

IO biomarker • Journal • Review • Oncology • Targeted Protein Degradation • CD8 • PD-L1 • TIGIT

Dissecting SUMOylation-mediated mechanisms that regulate AAV transgene expression (ASGCT 2026) - "Using the SUMOylation inhibitor TAK-981, we previously showed significant enhancement of rAAV-mediated transgene expression in cultured cells and in mice, representing primarily episomal vector genomes (Seleme, Kasimsetty 2025)...Further studies using these cell lines will provide a model system for mechanistic studies to determine how inhibition of SUMOylation impacts transgene expression of AAV genomes. Conclusion Defining how SUMOylation influences AAV transduction and transcription may guide new strategies to improve AAV gene therapy by enabling lower vector doses and allowing controlled modulation of therapeutic gene expression."

Gene Therapies

Reshaping tumor immunity by targeting SUMOylation: A novel immunotherapeutic strategy. (PubMed, Biochim Biophys Acta Rev Cancer) - "Consequently, pharmacological inhibition of the SUMO pathway, exemplified by the first-in-class inhibitor TAK-981, has emerged as a promising therapeutic strategy. Such inhibitors can reverse immune suppression by enhancing type I interferon signaling, augmenting antigen presentation, and reinvigorating anti-tumor immunity. In this review, we synthesize current understanding of how SUMOylation governs the function and polarization of critical immune cells within the TIME, and explore the therapeutic potential of SUMO-targeting inhibitors in cancer treatment, aiming to provide novel theoretical insights and innovative strategies to advance cancer therapy."

Journal • Review • Immunology • Infectious Disease • Oncology • Targeted Protein Degradation

SUMOylation Inhibitor TAK-981 Alleviates Hallmark Features of Preeclampsia Related to High Glucocorticoid Exposure by Inhibiting Placental Oxidative Stress in Rats. (PubMed, Antioxidants (Basel)) - "A rat PE model was established by dexamethasone (DEX) treatment from pregnancy day 7.5-17.5. Our findings indicate that protein SUMOylation is one of the key events in PE, particularly in that associated with high glucocorticoid exposure. Targeting placental SUMOylation might be a promising therapeutic strategy for PE."

Journal • Preclinical • Gynecology • Renal Disease

Pharmacodynamic analysis from a phase 1/2 study of subasumstat (TAK-981) as single agent in patients (pts) with advanced/refractory metastatic solid tumors (AACR 2024) - P1/2 | "Background Subasumstat (TAK-981, suba) is a first-in-class innate immunity enhancer that unlocks innate/adaptive immune responses to target tumors through SUMOylation inhibition, which may enhance antitumor activity by restoring endogenous type 1 IFN signaling in immune cells. Our findings support continued development of suba in solid tumors. Suba is being evaluated in combination with pembrolizumab in NSCLC, cervical cancer, and melanoma (NCT04381650)."

Clinical • IO biomarker • Metastases • P1/2 data • PK/PD data • Cervical Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • ITGAX • PD-L1

Targeting the MYC-SUMO axis with TAK-981 reverses immune suppression and restores antigen presentation in osteosarcoma (AACR 2026) - "MYC drives immune suppression in OS through SUMO-dependent repression of antigen-presentation and innate immune pathways. Targeting the MYC-SUMO axis with TAK-981 converts the TME from immune-cold to immune-inflamed and enhances immunotherapy responses, supporting TAK-981-based combinations as a promising strategy for MYC-driven OS."

IO biomarker • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • G3BP1 • IFNA1 • MYC • PSMD4 • PTPRC • SAE1 • TARDBP • UBE2I

Combining SUMO inhibition and irinotecan increases pancreatic cancer cytotoxicity (AACR 2026) - "We hypothesized that combining IRI with Subasumstat (SST—a SUMOi agent) would synergize in reducing Top-1 efficacy, leading to augmented apoptosis. Human single cell RNA sequencing (scRNASeq): using the Human Pancreatic Cancer Single-Cell Atlas to identify SUMO2/3 expressing cancer cells after FOLFIRNINOX... SST+IRI constitutes a promising combination treatment for PDAC with synergistic PDAC cytotoxicity observed in both murine and human models. Clinically, SST could serve as an adjunct to FOLFIRINOX or SST+IRI could be an alternative 2nd line treatment with potential to include a RAS inhibitor."

Oncology • Pancreatic Cancer • Solid Tumor • CASP3

Identification of SUMO2 as a novel therapeutic target for synovial sarcoma (AACR 2024) - "We tested the SUMO2 inhibitor, TAK-981, a clinical stage small molecule inhibitor specific for E1 SUMO-activating enzyme (SAE), against a panel of SySa cell lines with HS-SY-II and SYO1 showing an EC50 in the low nanomolar range...Taken together, we developed an integrated computational and experimental screening approach to prioritize and validate selective dependencies in synovial sarcoma. Our studies identify SUMO2 as a novel, selective vulnerability in this cancer and since SUMO2 inhibitors are currently in Phase 1/2 clinical trials for other malignancies, our findings present a novel potential avenue for targeted treatment of synovial sarcoma."

Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • SS18 • SSX1

A newly developed patient-derived culture panel identifies precision therapies and pan-effective agents for head and neck squamous cell carcinoma (AACR 2024) - "Subsequent high-content imaging cell death assay further demonstrates a dose-dependent tipifarnib-induced cell death in HRASp.G13R-mutated PDC, but not in SNU-899; 2) TP53-EP300 co-mutated HNSCC-PDCs are most sensitive to cisplatin with ~340 nM sensitivity (mean IC50) among all PDCs tested, which is 22 times more sensitive than that reported in Genomics of Drug Sensitivity in Cancer (GDSC) HNSCC cell lines; 3) EGFR-AS1 (c.2361G>A)-germline mutated PDCs, and MAPK1-mutated PDCs, are both hypersensitive to EGFR inhibitors (EGFRi: erlotinib and mobocertinib), which independently credentialed gene-drug sensitivity relationships reported in exceptional responders in HNSCC clinical trials. These include 3 FDA-approved agents, TAK-981, Selinexor (a novel XPO1 inhibitor), and trametinib, as well as the preclinical agent JQ1. In conclusion, our pilot HNSCC-PDC drug screen identifies new gene-drug sensitivity relationships for HNSCC PM development and new pan-effective agents..."

IO biomarker • Late-breaking abstract • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • EP300 • HRAS • MAPK1 • PIK3CA • SHH

Pharmacological targeting of SUMOylation leads to cBAF complex stabilization and disruption of the synovial sarcoma signature (AACR 2024) - "As such, TAK-981 combined with standard-of-care chemotherapy enhances SOC-induced DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes, positioning it as a clinical candidate to treat this refractory cancer."

Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • SAE1 • SS18

SUMOylation networks drive glioblastoma stemness, microenvironmental remodeling, and resistance. (PubMed, Semin Oncol) - "Preclinical studies indicate that pharmacological inhibition of SUMOylation with agents like TAK-981, topotecan, or Paromomycin reduces tumor growth, reverses therapy resistance, and enhances radiosensitivity. Moreover, SUMO-related enzymes, such as UBA2, SENP1, and SUMO2/3, may serve as prognostic biomarkers. Understanding SUMOylation in GBM offers insights into tumor biology and identifies potential therapeutic targets to improve patient outcomes."

Journal • Review • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • Targeted Protein Degradation • CTNNB1 • HIF1A

Selective targeting of sumoylation disrupts mitochondrial homeostasis via TRAP1 to suppress growth of non-Hodgkin lymphoma (NHL) B-cells (AACR 2026) - "Collectively, our findings show that TAK-981 disrupts mitochondrial SUMOylation, leading to metabolic dysfunction and apoptosis in B-NHL cells. SUMO-dependent regulation of TRAP1 emerges as a mechanistic driver and a promising therapeutic vulnerability in lymphoma."

B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYC