indisulam (E7070) / Eisai - LARVOL DELTA

Transcriptomic and epigenetic profiling of neuroblastoma states in response to RBM39 degrader. (PubMed, Sci Data) - "To investigate the mechanisms underlying this plasticity, we subjected human and murine neuroblastoma models to repeated treatment with indisulam, a molecular glue compound that selectively degrades the splicing factor RBM39, until full drug resistance emerged...We present this resource to facilitate reuse by the scientific community. These datasets may support efforts to decipher lineage switching, identify regulators of therapy resistance, and discover potential therapeutic vulnerabilities in resistant neuroblastoma."

Journal • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • Targeted Protein Degradation • RBM39

RBM39 Contributes to MGMT Maintenance in Response to Temozolomide-Induced DNA Damage. (PubMed, Cancers (Basel)) - "Resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ) is a significant challenge in treating tumors with high MGMT expression, including MGMT-positive glioblastoma and neuroendocrine neoplasms. Functionally, combined indisulam and TMZ treatment significantly increased apoptosis and decreased clonogenic growth in neuroendocrine tumor cells. These findings identify MGMT as a downstream target of RBM39 in MGMT-expressing cancer cells and highlight the therapeutic potential of co-targeting RBM39 and MGMT to overcome resistance to alkylating chemotherapy."

Journal • Brain Cancer • Endocrine Cancer • Glioblastoma • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Solid Tumor • MGMT • RBM3 • RBM39

The RNA-binding protein RBM39 scaffolds an m⁶A-dependent RNA decay complex that destabilizes Tat transcripts and restricts HIV-1 reactivation. (PubMed, PLoS Biol) - "Genetic or pharmacological degradation of RBM39 (using the clinically explored molecular glue indisulam) potently reactivates latent HIV-1 in J-Lat cell models, primary CD4⁺ T cells from people living with HIV-1 (PLWH), and synergizes with established LRAs (Bryostatin-1, JQ-1, SAHA) to broadly activate proviral reservoirs...In addition to establishing RBM39 as a promising therapeutic target for addressing the limitations of current "shock and kill" strategies, our findings establish a novel mechanistic framework for m⁶A-dependent regulation of viral gene expression. This framework may serve as a valuable reference for investigating similar regulatory mechanisms in other latent viral infections or oncogenic processes where RNA methylation plays a pivotal role."

Journal • Human Immunodeficiency Virus • Infectious Disease • Oncology • Targeted Protein Degradation • CD4 • DDX5 • RBM39 • YTHDC1

Targeting RBM39-MEK5 Axis Synergizes with Bortezomib to Inhibit Multiple Myeloma Malignancy (ASH 2023) - "Mechanistically, shRNA-mediated knockdown or Indisulam-mediated degradation of RBM39 caused extensive altered splicing, including mis-splicing of MEK5. Targeting RBM39 or MEK5 could not only inhibit MM malignancy, but also enhance the cytotoxicity of bortezomib for MM."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • RBM39 • SDC1

Regulation of Alternative Splicing in B-Cell ALL By DYRK1A (ASH 2023) - "We also found that indisulam and its analogs, which lead to DCAF15-mediated degradation of RBM39, suppressed the growth of B-ALL cells in vitro and in vivo. Ectopic expression of RBM39 partially rescued the growth inhibition upon dinaciclib and EHT 1610 treatment suggesting downregulation of RBM39 is the key event in drug targeting. Together, our results reveal that DYRK1A controls RNA splicing by regulating the SF3B1-RNA Pol II interaction and that RBM39 is a therapeutic target in B-ALL."

Developmental Disorders • Genetic Disorders • RBM39 • SF3B1 • SRSF2 • STAT3 • UPF1

RNA Splicing as a Therapeutic Vulnerability in Therapy-Refractory Multiple Myeloma. (PubMed, Blood Cancer Discov) - "Using the RBM39 degrader indisulam, they show that therapeutic modulation of RNA splicing factors is a potential treatment strategy for patients with therapy-resistant multiple myeloma. See related article by Kamiya et al., p. XX."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • RBM39

NovumRNA: Accurate prediction of non-canonical tumor antigens from RNA sequencing data. (PubMed, iScience) - "Finally, our investigation of glioblastoma cell lines demonstrated increased ncTSAs burden upon indisulam treatment, and detection by NovumRNA of therapy-induced ncTSAs, which we could validate experimentally. These findings underscore the potential of NovumRNA for identifying synergistic drugs and novel therapeutic targets for immunotherapy, which could ultimately extend its benefit to a broader patient population."

IO biomarker • Journal • Tumor mutational burden • Brain Cancer • Colorectal Cancer • Glioblastoma • Oncology • Solid Tumor • TMB

Network-driven identification of indisulam neo-substrates for targeted protein degradation. (PubMed, Mol Omics) - "Our work employs established network resources and analytical methods to effectively identify direct targets of the indisulam molecular glue degrader. This approach is readily adaptable for exploring novel targets across other molecular glue systems, enhancing its applicability and value to the drug discovery community."

Journal • Targeted Protein Degradation • RBM39

A comprehensive immune cycle enhancement strategy for alternative splicing-mediated endogenous Tumor neoantigens generation and delivery. (PubMed, Mater Today Bio) - "To address these challenges and augment antitumor immune responses, we developed the innovative core-shell nanoparticle system BaTiO3-indisulam@PD1-cell Membrane Nanoparticles (BI@PCM NPs)...Integration of Pd1 cell membrane coating provides enhanced targeting capabilities and significantly amplifies cytotoxic T-cell activation. By strengthening multiple immune cycle steps, BI@PCM exhibits immense potential to revolutionize personalized tumor immunotherapy and provide a robust solution for osteosarcoma treatment."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity. (PubMed, Nat Commun) - "Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances the anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states."

Journal • Neuroblastoma • Oncology • Solid Tumor • RBM39

RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity (Nature) - "We show that cancer cells not only undergo a bidirectional switch between adrenergic and mesenchymal states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. These cell state alterations are coupled with epigenetic reprogramming and dependency switching of cell state–specific transcription factors, epigenetic modifiers, and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances the anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states."

Preclinical • Neuroblastoma

Alectinib enhances response to RBM39 degradation via SRPK1 inhibition in high-risk neuroblastoma (EACR 2025) - "Indisulam, a potent degrader of RNA Binding Motif 39 (RBM39), disrupts RNA splicing and affects multiple cellular pathways. Our findings highlight that targeting complementary RNA splicing components SRPK1 and RBM39 offers a promising strategy for enhancing therapeutic efficacy and improving outcomes in high-risk neuroblastoma. This approach represents a potential advancement in the treatment of this challenging paediatric cancer."

Neuroblastoma • Oncology • Pediatrics • Solid Tumor • ALK • MYCN • RBM39 • SRPK1

Indisulam evokes T cell dependent cytotoxicity through mis-splicing in neuroblastoma. (EACR 2025) - "Our findings indicate that splicing inhibitors can induce production of transcripts common across neuroblastoma and other cancer cell lines. We aim to identify the presence of the immunogenic neopeptides, these mis-spliced transcripts code for, through immunopeptidomics. Our findings show that combination of splicing inhibitors with immunotherapies, such as vaccines, could leverage these immunogenic neoantigens, paving the way towards the development of highly efficacious and specific immunotherapies against solid pediatric tumours."

IO biomarker • Melanoma • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • Targeted Protein Degradation • CD8 • MYCN • RBM39

Advancing treatment in high-grade serous ovarian cancer through targeting of RNA splicing (EACR 2025) - "Introduction: The RNA binding protein RBM39 regulates alternative splicing and is targeted by the small aryl sulphonamides E7070 (indisulam) and E7820. An increase in antigen-presenting cells (APCs) such as cDCs may reflect a rise in neoantigens available for identification, aligning with our hypothesis. Overall, these results could suggest a complex immunomodulatory effect following RBM39 depletion, which could potentially benefit patients receiving immunotherapies."

High Grade Serous Ovarian Cancer • Neuroblastoma • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • RBM39

Targeting RNA splicing as a novel therapeutic strategy in ovarian high-grade serous carcinoma (EACR 2025) - "RNA splicing interference with molecular protein degraders offers new strategies to sensitise to therapies in resistant ovarian HGSC through a dual action of targeting DNA damage repair and splicing-derived neoantigens"

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • HRD • RBM39

IDENTIFICATION, EVALUATION AND IN VITRO VALIDATION OF IMMUNOGENIC NEOEPITOPES PREDICTED FROM ACUTE MYELOID LEUKEMIA (AML) BLASTS AFTER EXPOSURE TO SPLICING INHIBITOR DRUGS (EHA 2025) - "Thirteen primary AML samples were treated for 6h with splicing inhibitors (indisulam, pladienolide B, H3B-8800, madrasin) to enhance neoantigen generation. The in silico identification of neoantigens and their in vitro immunogenic validation using a model of mMoDCs and naïve CD8+ T cells may provide valuable insights for the development of targeted immunotherapeutic strategies in AML. Further investigation is warranted to explore the translational potential of this study."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD8 • HLA-A • IFNG • SF3B1 • SRSF2 • U2AF1

CLUSTERING ANALYSIS OF ALTERNATIVE SPLICING IN B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA IDENTIFIED TARGETABLE SUBTYPE WITH GLOBAL SPLICING DEFECTS (EHA 2025) - "This finding suggested that the GSD subtype can be targeted by RBM39 degradation using indisulam.Exon skipping of U2AF1 as a loss-of-function event was recurrently detected in the GSD subtype... Our study confirmed AS dysregulation in adult BCP-ALL caused by post-transcriptional regulation of splicing factors. The identification of a GSD subtype in BCP-ALL based on AS event clustering enables tailored therapeutic strategies. Elucidating the genetic landscape and the preferential sensitivity to splicing-targeting drugs of this subtype could improve outcomes for adult patients with limited therapeutic options and frequent treatment resistance."

Clinical • IO biomarker • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • RBM39 • U2AF1

Methylation of RBM39 by PRMT6 enhances resistance to Indisulam in non-small cell lung cancer by promoting alternative splicing of proto-oncogenes. (PubMed, PLoS Biol) - "Inhibiting PRMT6 with MS023 or mutating the RBM39 methylation site enhances Indisulam sensitivity in NSCLC and significantly improves its anti-tumor efficacy. Our findings identify methylated RBM39 as a key biomarker of Indisulam resistance and suggest a potential therapeutic strategy for NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • PRMT6 • RBM39

RBM39 Promotes Base Excision Repair to Facilitate the Progression of HCC by Stabilising OGG1 mRNA. (PubMed, Cell Prolif) - "Moreover, data suggested that RBM39 degradation, combined with oxidative damage, could be more effective for HCC treatment than monotherapy, both in vitro and in xenograft mice models. Overall, we demonstrated that RBM39 regulated OGG1 stabilisation and improved BER efficiency, suggesting that combining the RBM39 degradant indisulam with the oxidising agent KBrO3 could be an emerging strategy for HCC treatment."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • OGG1 • RBM3 • RBM39

RBM39 shapes innate immunity by controlling the expression of key factors of the interferon response. (PubMed, Front Immunol) - "SiRNA knockdown and indisulam treatment were used to study the role of RNA-binding motif protein 39 (RBM39) in innate immunity upon poly(I:C) or cytokine treatment and viral infections...We identified RBM39 as a regulatory factor of cell intrinsic innate immune signaling. Depletion of RBM39 impaired TLR3, RIG-I/MDA5, and IFN responses by affecting the basal expression of key pathway components."

IO biomarker • Journal • Infectious Disease • IFIH1 • RBM3 • RBM39 • STAT1 • TLR3

Indisulam Shows an Anti-Cancer Effect on HPV+ and HPV- Head and Neck Cancer. (PubMed, Cancers (Basel)) - " These findings suggest that targeting alternative splicing via indisulam may be a promising therapeutic approach for HPV+ cancers. Further research is required to establish indisulam as a viable anti-cancer treatment in clinical settings."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • RBM39

The RBM39 degrader indisulam inhibits acute megakaryoblastic leukemia by altering the alternative splicing of ZMYND8. (PubMed, Cell Biosci) - "Indisulam is a promising therapeutic candidate for AMKL and the RBM39-mediated ZMYND8 splicing plays an important role in promoting the development of AMKL."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • DDB1 • RBM3 • RBM39 • ZMYND8

RNA-binding motif protein RBM39 enhances the proliferation of gastric cancer cells by facilitating an oncogenic splicing switch in MRPL33. (PubMed, Acta Pharmacol Sin) - "Genetic manipulation and pharmacological treatment with the RBM39 degrader indisulam demonstrated that RBM39 regulated cell proliferation by influencing the splicing switch of MRPL33 in gastric cancer cells and a xenograft mouse model. Our findings indicate that RBM39 regulates the oncogenic splicing of MRPL33 and suggest that it may serve as a potential therapeutic target for gastric cancer."

Journal • Gastric Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • RBM39

Alternative Splicing: A Key Regulator in T cell Response and Cancer Immunotherapy. (PubMed, Pharmacol Res) - "AS modulators such as PRMT5 inhibitor GSK3326595 enhance immunotherapy efficacy by upregulating MHC class II expression and promoting T cell infiltration, while RBM39 inhibitor indisulam induces tumor-specific neoantigens. Future efforts should focus on refining AS-targeting therapies, identifying predictive biomarkers, and integrating these approaches into clinical applications. This review highlights the therapeutic potential of AS modulation in cancer immunotherapy and its implications for advancing precision oncology."

IO biomarker • Journal • Review • Immune Modulation • Immunology • Oncology • CD8 • RBM39

The Influence of Indisulam on Human Immune Effector Cells: Is a Combination with Immunotherapy Feasible? (PubMed, Pharmaceutics) - "While moDC maturation was also rather resistant, T cell priming was almost completely abolished at a concentration of 10 µM. These effects should be considered in possible future combinations of immunotherapy with the mRNA splicing inhibitor indisulam."

Journal • Oncology • CD4 • CD8