E7820 / Eisai - LARVOL DELTA

E7820, an Anti-Cancer Sulfonamide, in Combination with Venetoclax in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial (ASH 2023) - P2 | "Secondary endpoints include overall and event-free survival. Correlative biomarker and pharmacodynamic parameters will be assessed as exploratory endpoints including effects on RBM39 protein levels, changes in global and key target splicing events, and evaluation of DCAF15 mRNA levels and response to therapy."

Clinical • Combination therapy • IO biomarker • P2 data • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BCL2 • MCL1 • RBM39 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

Spliceosome-Targeting Therapies in SF3B1-Mutated Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis of Clinical Efficacy and Safety (SOHO 2026) - "Eligible studies included phase 1 and phase 2 trials enrolling adults with MDS who had documented SF3B1 mutations and were treated with spliceosome-targeting agents, including SF3B1 modulators (H3B-8800) or spliceosome-associated inhibitors (E7820, selinexor). Spliceosome-targeting therapies demonstrate limited single-agent efficacy in SF3B1-mutated MDS, with no consistent IWG responses from direct modulators and a post hoc signal from XPO1 inhibition requiring prospective validation. Adequately powered, SF3B1-stratified randomized trials incorporating biomarker-guided patient selection are urgently needed to define the role of this therapeutic class. ASH: American Society of Hematology, CI: confidence interval, EHA: European Hematology Association, IWG: International Working Group, MDS: myelodysplastic syndromes, PICOS: patient (or population or problem), intervention, comparison, outcome, study design, RBC-TI: red blood cell transfusion independence, SF3B1: splicing..."

IO biomarker • Retrospective data • Review • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • SF3B1 • XPO1

AI-assisted design and virtual profiling of targeted degraders for pancreatic cancer therapy via PROTAC technology. (PubMed, Am J Cancer Res) - "The results identified CLTTMPBA-linker-E7820 as a computationally prioritized PROTAC architecture with favorable predicted binding behavior, residue-level interaction patterns, and simulated ternary-complex stability. Importantly, this study is entirely computational and should be interpreted as an early-stage in silico prioritization framework rather than experimental evidence of BRD4 degradation or anticancer efficacy. The proposed BRD4-DCAF15 PROTAC candidates represent lead hypotheses that require biochemical, cellular, pharmacological, and in vivo validation, including confirmation of target engagement, ternary-complex formation, proteasome-dependent BRD4 degradation, downstream transcriptional modulation, pancreatic cancer cell inhibition, selectivity, pharmacokinetics, toxicity, and antitumor efficacy."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • BRD4

E7820, an anti-cancer sulfonamide, degrades RBM39 in patients with splicing factor mutant myeloid malignancies: a phase II clinical trial. (PubMed, Leukemia) - No abstract available

Journal • P2 data • Hematological Malignancies • Oncology • RBM39

Assessing the Stability of Molecular Glues with Weighted Ensemble Simulations. (PubMed, J Chem Theory Comput) - "Using this strategy, we generated unbinding trajectories of the DCAF15-RBM39 system with small molecules E7820, Indisulam, and several other Indisulam analogs. We were able to observe distinctly different behaviors between systems with different glues, which was in agreement with their reported EC50 values. We believe this approach could aid drug discovery efforts by expanding the set of druggable targets and improving the success rate of molecular glue development."

Journal • Oncology • Targeted Protein Degradation • RBM39

Modality strategy in Eisai drug discovery: challenges toward next-generation therapeutics using proximity-inducing compound (PubMed, Nihon Yakurigaku Zasshi) - "Eisai's entry into this field was driven by the discovery of the unique mechanism of action of Indisulam and E7820, which function as MGD to degrade RBM39 via DCAF15 recruitment. PIC represent a transformative modality that expands the druggable proteome and offers new therapeutic options for intractable diseases. This article outlines Eisai's efforts in PIC-based drug discovery, with a focus on targeted protein degradation and future perspectives."

Journal • Review • Oncology • Targeted Protein Degradation • CEACAM6 • RBM39

Favorable DMPK properties enable development of a novel arylsulfonamide RBM39 molecular glue degrader, PPI-101, for the treatment of neuroblastoma (AACR 2026) - "This study defines, for the first time, the in vivo PK/PD relationships governing RBM39 degradation and demonstrates that favorable distribution properties can markedly enhance therapeutic index. PPI-101 emerges as a potent and safer RBM39 degrader candidate for neuroblastoma therapy, warranting GLP toxicology and IND-enabling development."

Neuroblastoma • Oncology • Solid Tumor • IL17RB • RBM39

A systematic mass spectrometry-based chemoproteomic platform (chomiXdegradeTM) for molecular glue degrade discovery and mechanistic dissection (AACR 2026) - "As a proof of concept, we performed a comparative analysis of two aryl-sulfonamide MGs, E7820 and indisulam, which induce RBM39 degradation via recruitment to the DCAF15 E3 ligase but have not been systematically compared...Pharmacological inhibition with MG132 or the cullin-RING E3 ligase inhibitor MLN4924 markedly suppressed RBM39 degradation, confirming a proteasome- and CRL-dependent mechanism...Furthermore, a living-cell TurboID proximity labeling strategy enabled direct proteomic capture of MG-induced ternary complexes, with reciprocal enrichment of RBM39, DCAF15, and associated interaction partners. Collectively, these results establish ChomiXDegrade™ as a scalable and versatile chemoproteomic framework for molecular glue degrader discovery and systematic characterization of substrate-E3 ligase interactions."

Late-breaking abstract • Oncology • RBM39

Study protocol for a phase I investigator-initiated clinical trial of E7820 in Japanese patients with unresectable solid tumours: CIRCUS trial (NCCH2303). (PubMed, Jpn J Clin Oncol) - "Based on these findings, the CIRCUS trial, a multicentre investigator-initiated phase I study, was initiated to assess the safety, tolerability, and preliminary efficacy of E7820 in Japanese patients with unresectable solid tumours. If the proof of concept is demonstrated in biomarker-defined cohorts, E7820 may be repositioned for selected patients, providing insights into the development of previously intractable compounds."

Journal • P1 data • Endometrial Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HRD • RBM39

Targeting Poly(U) Binding Splicing Factor 60 (PUF60): A Small-Molecule Inhibitor Shows Anti-Leukemic Activity and Impacts Cell Cycle in Leukemia Models (ASH 2024) - "In comparison, E7820, an RBM39 degrader, increased G2/M phase in both NKM-1 and K562...Upregulation of cholesterol biosynthesis may be a feedback loop to counteract the inhibition of PUF60 by SF2-69. Further optimization of SF2-69 will allow us to develop more effective and selective chemical probes for studying the role of PUF60 overexpression in leukemia and the potential use of PUF60 inhibitors in MDS and AML cells carrying splicing factor mutations."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • CDC25C • GNRP • PLK1 • RASGRF1 • RBM39 • SF3B1 • SRSF2 • U2AF1

The integrin α2-osteoclast axis: a key driver of bone destruction and therapeutic target in osteosarcoma. (PubMed, J Transl Med) - "This study uncovered that ITGA2 drives osteosarcoma progression and aggravates osteolysis via the "ITGA2-osteoclast axis", with high expression predicting poor outcomes. Mechanistically, ITGA2 promoted tumor invasion and bone metabolism imbalance by regulating osteoclastogenic signaling, while its targeted inhibition synergistically suppresses tumor growth and restores bone homeostasis, highlighting ITGA2 as a pivotal therapeutic target for osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • ITGA2 • MMP9

Targeting Integrin α2 to Overcome Imatinib Resistance in Chronic Myeloid Leukemia Cells. (PubMed, Biomolecules) - "Our findings showed that ITGA2 is overexpressed in K562R cells and ITGA2 inhibitor E7820 (2.5 µM) treatment significantly decreased cell viability and induced apoptosis in both sensitive and resistant cells. Flow cytometry confirmed ITGA2 inhibition at the protein level, and rhodamine assays revealed reduced MDR1 activity in treated cells. These results demonstrate that targeting ITGA2 may overcome imatinib resistance and offer a novel therapeutic strategy for CML."

IO biomarker • Journal • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ABCB1 • ABL1 • BAX • BCL2 • BCR • ITGA2

ITGA2 Mediates the Resistance of Hepatocellular Carcinoma to Lenvatinib by Activating the AKT/FOXO3A Signaling Pathway. (PubMed, Cancers (Basel)) - "The global incidence of primary liver cancer ranks sixth among malignant tumors, while its mortality rate ranks third and is the second leading cause of cancer-related deaths in China [...]."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • ITGA2

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

A Study of E7820 in People With Bone Marrow (Myeloid) Cancers (clinicaltrials.gov) - P2 | N=12 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

Targeting RBM39 suppresses tumor growth and sensitizes osteosarcoma cells to cisplatin. (PubMed, Oncogene) - "Importantly, our results reveal that the pharmacological depletion of RBM39 by using the anti-cancer aryl sulfonamide (E7820), a drug known for its oral bioavailability and safe administration, effectively represses osteosarcoma growth and sensitizes osteosarcoma cells to cisplatin treatment both in vitro and in vivo. Our findings unveil the crucial role of RBM39 in modulating tumor growth and cisplatin sensitivity in osteosarcoma cells, suggesting that the combination of aryl sulfonamides with cisplatin may benefit patients with osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • DKK1 • RBM39

Recent advances in anticancer mechanisms of molecular glue degraders: focus on RBM39-dgrading synthetic sulfonamide such as indisulam, E7820, tasisulam, and chloroquinoxaline sulfonamide. (PubMed, Genes Genomics) - "Recent research on tasisulam reveals its potential in cancer therapy by targeting RBM39 degradation through DCAF15-mediated pathways. Understanding these mechanisms could lead to new treatments that affect alternative splicing and improve cancer therapies Overall, although these drugs exhibit promising mechanisms of action, further research is required to optimize their clinical efficacy and safety."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Hematological Malignancies • Metabolic Disorders • Neuroblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • RBM39

Investigator-initiated clinical studies to be launched following confirmation of tumor shrinkage induced by the targeted protein degrader E7820 using J-PDX (Japanese cancer patient-derived tissue transplantation models) (Eisai Press Release) - "Tumor-agnostic efficacy evaluation of Eisai's targeted protein degrader E7820 was performed using patient-derived xenograft (PDX) models created by transplanting tumor tissue derived from patients into immunodeficient mice (pancreatic cancer, bile duct cancer, gastric cancer, and uterine cancer), which observed tumor shrinkage in 38.1% for overall, 58.3% for bile duct cancer, and 55.6% for uterine cancer....Based on the cancer types and predictive biomarkers associated with E7820 efficacy revealed by this study, an investigator-initiated clinical study will be launched at the National Cancer Center Hospital and the National Cancer Center Hospital East for the purposes of safety evaluation including the tolerability in Japanese patients, and exploratory efficacy evaluation."

New trial • Preclinical • Cholangiocarcinoma • Gastric Cancer • Pancreatic Cancer • Uterine Cancer

A Study of E7820 in People With Bone Marrow (Myeloid) Cancers (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2024 ➔ Aug 2025 | Trial primary completion date: Aug 2024 ➔ Aug 2025

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency. (PubMed, NPJ Precis Oncol) - "E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. Furthermore, E7820, in combination with olaparib, exerted a synergistic effect, and E7820 was even effective in an olaparib-resistant cell line. In conclusion, HRD is a promising predictive biomarker of E7820 efficacy and has a high potential to improve the prognosis of patients with HRD-positive cancers."

Journal • Synthetic lethality • Oncology • Solid Tumor • Targeted Protein Degradation • BAP1 • BRCA1 • BRCA2 • HRD • RBM39

Native mass spectrometry of complexes formed by molecular glues reveals stoichiometric rearrangement of E3 ligases. (PubMed, Analyst) - "We have shown that nMS can unambiguously identify complexes formed between the CRBN : DDB1 E3 ligase and the POI GSPT1 upon the addition of lenalidomide, pomalidomide or thalidomide. Ternary complex formation was also identified involving the DCAF15 : DDA1 : DDB1 E3 ligase in the presence of MG (E7820 or indisulam) and POI RBM39. Moreover, we uncovered that the DCAF15 : DDA1 : DDB1 E3 ligase self-associates into dimers and trimers when analysed alone at low salt concentrations (100 mM ammonium acetate) which dissociate into single copies of the complex at higher salt concentrations (500 mM ammonium acetate), or upon the addition of MG and POI, forming a 1 : 1 : 1 ternary complex. This work demonstrates the strength of nMS in TPD research, reveals novel binding mechanisms of the DCAF15 E3 ligase, and its self-association into dimers and trimers at reduced salt concentration during structural analysis."

Journal • Targeted Protein Degradation • CRBN • DDB1 • GSPT1 • RBM39

FOLFIRI Alone Versus FOLFIRI Plus Bevacizumab Versus FOLFIRI Plus E7820 as Second-Line Therapy in Patients With Locally Advanced or Metastatic Colorectal Cancer (clinicaltrials.gov) - P1/2 | N=5 | Terminated | Sponsor: Eisai Inc. | Completed ➔ Terminated; The study was terminated early as the combination of E7820 and FOLFIRI was deemed to be not tolerable, hence no efficacy analysis was conducted.

Metastases • Trial termination • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study of E7820 in People With Bone Marrow (Myeloid) Cancers (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2023 ➔ Aug 2024 | Trial primary completion date: Aug 2023 ➔ Aug 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • IDH1 • SF3B1 • SRSF2 • U2AF1 • ZRSR2

Oxalamide containing compounds degrade cellular RBM39 and CENP-I (ACS-Fall 2023) - "A series of sulphonamides, including Indisulam and E7820, act as molecular glues between RBM39 and DCAF15, leading to selective degradation of RBM39. CENP-I is a member of centromere proteins, which is critically important for accurate chromosome segregation and mitosis. Our data suggest that molecular glue CB039-promoted degradation of CENP-I plays an important role in its cell cycle arrest function."

Acute Myelogenous Leukemia • Oncology • Targeted Protein Degradation • CENPI

A Phase II trial evaluating E7820 in patients with AML with splicing factor mutations (YouTube) - "In this video, Eytan Stein, MD...discusses a Phase II study evaluating the safety and efficacy of E7820 in patients with acute myeloid leukemia (AML) with splicing factor mutations (NCT05024994). Although the clinical efficacy of this agent was limited, Dr Stein highlights the promising biological activity observed and the possibility of exploring combination approaches to augment the activity of E7820. This interview took place at the 64th ASH Annual Meeting and Exposition congress held in New Orleans, LA."

Interview • Video