dimethylamino micheliolide (ACT001) / Accendatech - LARVOL DELTA

Orthotopic PDX modeling and preclinical therapeutic evaluation in pediatric ependymoma (EANO 2026) - "A targeted drug panel based on molecular alterations in ST-EPN, including CBL0137 (epigenetic inhibitor), ACT001 (NF-κB inhibitor), dovitinib and lenvatinib (VEGFR inhibitors), and entinostat and quisinostat (HDAC inhibitors) was evaluated for cytotoxicity in vitro using Alamar Blue and clonogenic assays. These orthotopic ST-EPN PDX models represent a reliable preclinical platform, enabling evaluation of molecularly guided combination therapies for pediatric ST-EPN with ZFTA-RELA fusion. Dovitinib emerged as a potential new treatment for RELA fused EPN."

Preclinical • Ependymoma • Oncology • Solid Tumor • RELA • ZFTA

Sequential multi-agent therapy eradicates tumours in preclinical models of Diffuse Midline Glioma (EANO 2026) - "Inspired by the curative "Total Therapy" approach in ALL, we hypothesised that a sequentially administered multi-agent regimen could achieve meaningful benefit in DMG by targeting key vulnerabilities: epigenetic/chromatin (CBL0137-Panobinostat, CP), polyamine metabolism (DFMO-AMXT1501, DA), and the NFκB pathway (ACT001). This rationally designed sequential multi-agent "Total Therapy" approach achieves profound tumour regression and long-term survival in aggressive DMG preclinical models. The strategy warrants further optimisation and clinical translation, offering new hope for children with this devastating disease."

Preclinical • Acute Lymphocytic Leukemia • Brain Cancer • Diffuse Midline Glioma • Glioma • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

ACT001 suppresses ox-LDL-mediated macrophage ferroptosis via activating the NRF2 pathway: An in vitro mechanistic study relevant to atherosclerosis. (PubMed, Exp Ther Med) - "In conclusion, ACT001 effectively ameliorated ox-LDL-triggered ferroptosis in RAW264.7 macrophages through facilitating NRF2 nuclear translocation and upregulating GPX4/xCT expression. The present in vitro findings revealed a molecular mechanism linking ACT001 to the inhibition of macrophage ferroptosis, offering preliminary cell-level evidence of the ACT001 therapeutic potential against macrophage-driven pathological events in atherosclerosis."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • GPX4 • SLC7A11

Micheliolide and ACT001 as Covalent Modulators of Inflammation-Redox-Metabolism Networks in CNS Disorders: An Evidence-Stratified Review of Mechanisms and Translational Challenges. (PubMed, Drug Des Devel Ther) - "MCL and ACT001 represent a promising covalent scaffold for modulating interconnected CNS networks, with glioblastoma as the most translationally advanced indication. Priorities include quantitative CNS pharmacokinetics, long-term safety of covalent pharmacology in post-mitotic neurons, and validation of metabolic-redox coupling in brain-resident cells via chemoproteomic and single-cell approaches."

Journal • Review • Brain Cancer • CNS Disorders • Glioblastoma • Immunology • Inflammation • Movement Disorders • Neuralgia • Neuromyelitis Optica Spectrum Disorder • Oncology • Pain • Parkinson's Disease • Rare Diseases • Solid Tumor • Vascular Neurology • GAPDH • KEAP1 • MYC • NLRP3 • PKM • STAT3 • TLR4

Proof-of-Concept Study of ACT001 in Adult Patients With Recurrent Glioblastoma Harbouring STAT3-High Signature (clinicaltrials.gov) - P2 | N=12 | Recruiting | Sponsor: National Neuroscience Institute | Trial completion date: May 2026 ➔ May 2027 | Trial primary completion date: May 2026 ➔ May 2027 | Suspended ➔ Recruiting

Enrollment open • Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Targeting MD2 in diseases: from structure and function to inhibitor development. (PubMed, Eur J Med Chem) - "Targeting MD2 has emerged as an important therapeutic strategy for human diseases. Currently, significant progress has been made in the development of MD2 inhibitors, among which ACT001, TAK-242, and eritoran have entered clinical studies for the treatment of diffuse midline glioma, alcoholic hepatitis and septic shock, etc. In this review, we provide a systematic summary of reported MD2 inhibitors, focusing on their structural characteristics, biological functions, binding modes with MD2, and the role of MD2 in related diseases, with the goal of providing reference for the development of novel anti-inflammatory drugs."

Journal • Review • Acute Lung Injury • Brain Cancer • Diffuse Midline Glioma • Fibrosis • Glioma • Immunology • Infectious Disease • Inflammation • Oncology • Respiratory Diseases • Septic Shock • Solid Tumor • TLR4

Sensitisation pathways revealed by CRISPR-based combinatorial dependency analysis in paediatric high-grade glioma (ISPNO 2026) - "Each cell line was transduced with a genome-wide knockout library and subsequently exposed to 11 different compounds, including FDA-approved agents (Trametinib, ONC201, Temozolomide, Ribociclib, Infigratinib, Avapritinib, Erlotinib, and Alpelisib) and additional pathway inhibitors (TP0184, ACT001 and Paxalisib). Finally, KEGG analysis of pan-therapy dependency genes identified significant enrichment of the ubiquitin system, spliceosome, kinetochore dephosphorylation, and mitotic checkpoint complex pathways, suggesting the presence of conserved, lineage-independent vulnerabilities across pHGGs. Together, these finding highlight the presence of a robust pan-dependency signature across drugs and points to conserved vulnerabilities that may offer complementary therapeutic opportunities."

Brain Cancer • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • Targeted Protein Degradation • PI3K

DMAMCL induces ferroptosis in neuroblastoma by targeting HMOX1 in MYCN-amplified subtypes whereas targeting STEAP3 in MYCN-nonamplified subtypes. (PubMed, Redox Rep) - "Dimethylaminomicheliolide (DMAMCL), a prodrug of Micheliolide (MCL), shows antitumor activity against NB, but its mechanisms remain unclear...DMAMCL induces ferroptosis in NB through MYCN-associated dual pathways, activating the NRF2/HMOX1 axis via KEAP1 binding in MYCN-amplified cells, while upregulating STEAP3 in MYCN-nonamplified cells. This provides new insights for DMAMCL application in treating NB subtypes with different MYCN levels."

Journal • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • HMOX1 • KEAP1 • MYCN • STEAP3

Therapeutic development of the clinically active compound ACT001 with Mcl-1 inhibitors for the treatment of paediatric diffuse midline glioma (ISPNO 2026) - P1 | "Mcl-1 inhibitors (MIK665 and AZD5991) showed the strongest synergy consistent with ACT001-mediated suppression of anti-apoptotic signalling...In vivo, ACT001, the Mcl-1 inhibitor S63845, and their combination each extended survival without evidence of synergy in orthotopic DMG models and reduced Ki67-positive tumour cells...Collectively, these findings indicate that ACT001 is a multi-targeted agent that disrupts NF-κB and apoptotic signalling while promoting oxidative stress and the unfolded protein response. Combining ACT001 with inhibitors of anti-apoptotic proteins represents a promising therapeutic strategy for patients with DMG."

Clinical • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • NQO1 • RELA

Targeted covalent drug discovery in paediatric diffuse midline glioma using chemoproteomics (ISPNO 2026) - "ABPP showed that MCL, the active metabolite of ACT001, a prodrug currently in clinical trials for DMG, engages SOX2, while the in-house compound JNSY1 binds histone H3...Conclusion These findings provide the first evidence that key DMG drivers H3K27M and SOX2 are directly tractable by CRCLs. By successfully executing a pipeline from discovery to preclinical evaluation, we highlight JNSY1 and MCL as promising covalent drug candidates for this lethal childhood cancer."

Brain Cancer • Diffuse Midline Glioma • Glioma • Pediatrics • Solid Tumor • SOX2

Development of orthotopic PDX models and discovery of targeted therapies in pediatric ependymoma (ISPNO 2026) - "Targeted agents were selected based on molecular alterations in relapsed zccs1304 tumors and assessed for therapeutic efficacy, including FACT inhibitor (CBL0137), NF-κB inhibitor (ACT001), VEGFR inhibitors (dovitinib, lenvatinib) and HDAC inhibitors (entinostat, quisinostat). Additionally, dovitinib in combination with CBL0137 or quisinostat significantly enhanced cytotoxicity in cultures. Our orthotopic ST-EPN PDX models offer a reliable preclinical platform for developing rational combination therapies for pediatric ST-EPN with ZFTA-RELA fusion."

Clinical • Ependymoma • Oncology • Pediatrics • Solid Tumor • RELA • ZFTA

A Study to Evaluate Safety and Efficacy of ACT001 and Anti-PD-1 in Patients With Surgically Accessible Recurrent Glioblastoma Multiforme (clinicaltrials.gov) - P1/2 | N=48 | Active, not recruiting | Sponsor: Accendatech USA Inc. | Recruiting ➔ Active, not recruiting | Phase classification: P1b/2a ➔ P1/2 | Trial completion date: Nov 2023 ➔ Dec 2026

Enrollment closed • Phase classification • Trial completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Phase II clinical study of ACT001 combined with radiotherapy in newly diagnosed pediatric diffuse intrinsic pontine glioma. (ASCO 2026) - P2 | "ACT001 combined with standard radiotherapy exhibits certain antitumor activity in the treatment of newly diagnosed pediatric DIPG, with improved OS compared to historical data, as well as a manageable safety profile and good tolerability. This regimen provides a new treatment option for pediatric DIPG and warrants further verification in larger-scale randomized controlled trials."

Clinical • P2 data • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Infectious Disease • Pediatrics • Respiratory Diseases • Solid Tumor

Traditional Chinese Medicine-Derived Active Ingredient and Formulation Therapy for Glioma: Multi-Target Mechanisms, Drug Delivery Systems, and Advances in Clinical Translational Research. (PubMed, Pharmaceuticals (Basel)) - "For clinical translation, a number of innovative drugs derived from TCM, such as elemene, cinobufagin, and ACT001, are currently under clinical investigation, with initial results showing efficacy in prolonging survival and improving quality of life. In the future, by integrating the analysis of multi-target synergistic mechanisms, promoting the clinical translation of intelligent drug delivery systems, and conducting high-quality clinical research on integrated Chinese and Western medicine, TCM is expected to provide a new generation of integrated treatment strategies for glioma that combines holistic and precision medicine."

Journal • Review • Brain Cancer • Glioma • Oncology • Solid Tumor

USP22 deubiquitinates and stabilizes ERK1/2 to promote colorectal cancer progression. (PubMed, Acta Pharmacol Sin) - "Moreover, we identified ACT001 as a novel USP22 inhibitor, and ACT001 induced substantial ERK1/2 ubiquitination and its subsequent degradation, efficiently suppressing the growth of CRC cells in vitro and in vivo by targeting USP22. Overall, this study revealed the mechanism underlying the role of hyperregulated ERK1/2 in CRC development, providing further insights into the pathology of CRC and the potential applicability of USP22-ERK1/2 as a therapeutic target in CRC."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • USP22

Therapeutic Potential of Micheliolide and ACT001 in Age-Related Diseases: Molecular Mechanisms and Clinical Prospects. (PubMed, Aging Dis) - "This paper summarizes the current mechanistic insight and disease-specific evidence regarding MCL/ACT001 and further evaluates their therapeutic repositioning potential for age-related diseases, including cardiovascular and cerebrovascular diseases, fibrotic conditions, immune disorders, metabolic diseases, and tumors. Additionally, we discussed key translational challenges."

Journal • Brain Cancer • Cardiovascular • CNS Disorders • Fibrosis • Glioblastoma • Immunology • Metabolic Disorders • Oncology • Solid Tumor • Vascular Neurology • AMPK • NLRP3 • STAT3

Proof-of-Concept Study of ACT001 in Adult Patients With Recurrent Glioblastoma Harbouring STAT3-High Signature (clinicaltrials.gov) - P2 | N=12 | Suspended | Sponsor: National Neuroscience Institute | Not yet recruiting ➔ Suspended

Trial suspension • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Parthenolide and Its Derivatives in the Treatment of Respiratory Tract Diseases: Therapeutic Effects and Molecular Mechanisms. (PubMed, Drug Des Devel Ther) - "We summarize the clinical translation progress of ACT001, including its safety and pharmacokinetic profiles, discuss emerging delivery systems such as micelles, and review the patent landscape of PTN derivatives. By integrating mechanistic insights with progress in clinical applications and drug delivery, this review provides a foundation for further mechanistic studies and supports the translational development of PTN-based therapies for respiratory disorders."

Journal • Review • Acute Lung Injury • Asthma • Immunology • Infectious Disease • Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • STAT3

ACT001 alleviates sepsis-induced acute lung injury by downregulating PANoptosis via the JAK2/STAT3 pathway. (PubMed, Inflamm Res) - "This study demonstrates that ACT001 mitigates sepsis-induced lung injury, likely by inhibiting PANoptosis through the suppression of the JAK2/STAT3 pathway. These findings provide new insights into the interplay between inflammatory cell death and JAK/STAT signaling, suggesting that ACT001 warrants further investigation as a potential therapeutic agent for sepsis-related ARDS."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Septic Shock • CASP3 • IGF2BP1 • IL1B • IL6 • TNFA • ZBP1

ACT001 synergizes with temozolomide-based chemoradiotherapy to cure refractory glioblastoma by targeting TNF-CXCL10-CD8+ T-cell immunity. (PubMed, Front Pharmacol) - "Pharmacological inhibition of the TNF signaling pathway with R-7050 completely abolished the synergistic efficacy of RT/TMZ/ACT001. Taken together, our results demonstrate that ACT001 combined with RT/TMZ can overcome the immunosuppressive barrier of GBM to achieve immune cure in GBM via TNF-CXCL10-CD8+ signaling, strongly suggesting the priority of combining ACT001 with RT/TMZ rather than with αPD-1 in clinical trials."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD8 • CXCL10 • TNFA

ACT001 synergizes with temozolomide-based chemoradiotherapy to cure refractory glioblastoma by targeting TNF-CXCL10-CD8+ T-cell immunity (Front Pharmacol) - "ACT001 combined with concurrent radiotherapy and temozolomide (RT/TMZ) exerted synergistic effects by suppressing tumor progression and extending animal survival. Importantly, the RT/TMZ/ACT001 regimen could achieve cure (long-term survival, >100 d, 26.7%) and immune cure (passing the tumor-rechallenge assay, >100 d, 12.5%) in G422TN mice."

Preclinical • Glioblastoma

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (SNO 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001's mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2

The development of ACT001 with Mcl-1 inhibitors as a novel combination therapy for the treatment of paediatric diffuse midline glioma (WFNOS 2025) - P1 | "Among the strongest were Mcl-1 inhibitors (Mcl1i-MIK665, Mcl1i-AZD5991) consistent with ACT001’s mechanism of downregulating anti-apoptotic signaling...In vivo, single-drug treatment of ACT001 or Mcl1i-S63845 extended survival in orthotopic DMG models and significantly reduced the number of Ki67-positive tumor cells...Our findings suggest that ACT001 is a multi-targeted agent acting on NF-κB and apoptotic signalling while inducing oxidative stress. The combination of ACT001 with anti-apoptotic protein inhibitors represents a promising treatment strategy for DMG patients."

Combination therapy • IO biomarker • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Pediatrics • Solid Tumor • BCL2 • NQO1 • SLC7A11 • SOD2

ACT001 alleviates MASLD through gut microbiota-bile acid-FXR axis in mice. (PubMed, Ann Med) - "ACT001 exerted a multifactorial therapeutic effect on MASLD, potentially linked to the regulation of the gut microbiota-BAs-FXR axis. Thus, it has the potential to be an effective treatment for MASLD."

Journal • Preclinical • Hepatology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology

A Randomized, Blinded, Placebo-controlled Phase III clinical Trial to Evaluate the Efficacy of ACT001 to Enhance the Result of Radiotherapy and the Reduction of Toxic and Side Effect of whole-Brain Radiotherapy for Patients with Brain Metastasis of Small Cell Lung Cancer (ChiCTR) - P3 | N=270 | Not yet recruiting | Sponsor: Affiliated Cancer Hospital of Shandong First Medical University (Shandong Institute of Cancer Prevention and Treatment and Shandong Cancer Hospital);

Adverse events • IO biomarker • New P3 trial • Brain Cancer • Lung Cancer • Oncology • Solid Tumor