Cu(II)ATSM / Collaborative Medicinal Development - LARVOL DELTA

Destabilized Soluble SOD1 Species as Potential Determinants of Disease Severity in Familial Amyotrophic Lateral Sclerosis. (PubMed, ACS Chem Neurosci) - "Neither CuATSM nor ebselen─targeting metal binding and disulfide formation, respectively─rescued fluorescence, suggesting broader defects in SOD1 maturation. Nevertheless, both compounds inhibited ferroptosis, a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation, in HT22 cells, indicating alternative neuroprotective mechanisms. These findings identify destabilized soluble SOD1 species as a key toxic entity in ALS and highlight the utility of GFP-tagged constructs for evaluating folding status and screening therapeutic candidates."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Ferroptosis and Cuproptosis in Cancer and Neurodegeneration: A Comprehensive Review of Modulation by Iron and Copper Chelators and Related Agents. (PubMed, Biomolecules) - "Conversely, neuroprotective strategies focus on site-specific chelation, utilizing brain-penetrant molecules like SK4 (targeting the LAT1 transporter) and radical trapping antioxidants like CuII(atsm)...Our analysis reveals a self-amplifying cycle of oxidative damage driven by metal-induced ATP depletion and glutathione exhaustion. By delineating the molecular machinery of iron and copper metabolism, this article provides a roadmap for leveraging regulated cell death to overcome apoptosis resistance in cancer and preserve neural integrity in chronic degeneration."

Journal • Review • CNS Disorders • Movement Disorders • Multiple Sclerosis • Oncology • Parkinson's Disease • Psychiatry • ATP7A • FDX1

MULTIMODAL POLYTHERAPY TARGETING BOTH ENDS OF THE MOTOR UNIT SYNERGISTICALLY IMPROVES NEUROMUSCULAR HEALTH IN ALS (ADPD 2026) - "We used the small molecule Cu(atsm) as a CNS penetrant neuroprotective agent and viral vector delivery of follistatin to promote muscle growth... By providing outcomes pertinent to the human disease and employing a clinically relevant treatment regimen, our results introduce multimodal polytherapy co-targeting skeletal muscle and neuroprotection as a new paradigm in the treatment of ALS."

Amyotrophic Lateral Sclerosis • CNS Disorders

NCOA4-Mediated Ferroptosis Drives cGAS-STING-Dependent Inflammation in Radiation Dermatitis: Protective Modulation by Cu-ATSM. (PubMed, Free Radic Biol Med) - "These findings identify the NCOA4-ferroptosis-cGAS-STING axis as a key pathogenic pathway linking redox imbalance to inflammation in radiation dermatitis. Cu-ATSM acts as a multimodal modulator that interferes with NCOA4-mediated ferritinophagy and mitigates ferroptosis-driven immune activation. This study establishes a mechanistic framework for ferroptosis-targeted interventions and supports Cu-ATSM as a promising therapeutic strategy for mitigating radiation-induced skin injury."

Journal • Dermatitis • Dermatology • Dermatopathology • Immunology • Inflammation • ACSL4 • IFNB1 • NCOA4 • STING

Local therapy with hypoxia-targeting radiopharmaceutical [64Cu]Cu-ATSM in high-grade glioma patient-derived xenograft models. (PubMed, Radiother Oncol) - "Local injection of [64Cu]Cu-ATSM into the tumor is a novel therapeutic strategy for HGG-PDX models, which combines hypoxia-targeted radiotherapy with PET-based treatment monitoring to address residual tumor cells and improve therapeutic outcomes."

Journal • Preclinical • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor

Pharmacological treatment of brain copper deficiency (Neuroscience 2025) - "Twenty-one days of 8 mg/kg daily CuATSM treatment restored Ctr1+/- mice copper levels in all CNS regions studied to equivalent levels observed in wild-type mice. Data from this study could inform the design of copper supplementation in preclinical research and clinical trials."

Amyotrophic Lateral Sclerosis • CNS Disorders • Movement Disorders • Parkinson's Disease

In vivo evaluation of local theranostic approach to high-grade glioma with hypoxia-targeting radiopharmaceutical 64Cu-ATSM (SNMMI 2025) - "Our clinical PET study has demonstrated that Cu-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) highly accumulated in the HGGs generally expressing hypoxia marker HIF-1α... The MTD of 64Cu-ATSM local treatment in mice was 3.7 MBq. After the local treatment with MTD, Imaging and autoradiography analyses demonstrated high tumor penetration, distribution, and retention of64Cu-ATSM within HGG PDX tumors, with highly expressed hypoxic markers of HIF-1α and BNIP3. A single 64Cu-ATSM local treatment significantly prolonged overall survival as well as potently induced DNA double-strand breaks and apoptosis in tumors."

Preclinical • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • HIF1A

Phase Ⅰ Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes (SNMMI 2025) - "Radioactive Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) was initially developed for positron emission tomography (PET) imaging of tumor hypoxia... Twenty patients were enrolled, and 18 were included in the full analysis set. Among them, 9 had glioblastoma, 4 had anaplastic astrocytoma, 1 had anaplastic oligodendroglioma, 2 had malignant meningioma, and 2 had metastatic brain tumors. Intravenously administered 64Cu-ATSM was well tolerated, with an MTD of 99 MBq/kg and no serious adverse events reported."

Clinical • PK/PD data • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Disorders • Epilepsy • Glioblastoma • Glioma • Heart Failure • Hematological Malignancies • Lymphoma • Meningioma • Oligodendroglioma • Oncology • Solid Tumor

Phase Ⅰ Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes (SNMMI 2025) - "Radioactive Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) was initially developed for positron emission tomography (PET) imaging of tumor hypoxia... Twenty patients were enrolled, and 18 were included in the full analysis set. Among them, 9 had glioblastoma, 4 had anaplastic astrocytoma, 1 had anaplastic oligodendroglioma, 2 had malignant meningioma, and 2 had metastatic brain tumors. Intravenously administered 64Cu-ATSM was well tolerated, with an MTD of 99 MBq/kg and no serious adverse events reported."

Clinical • PK/PD data • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Disorders • Epilepsy • Glioblastoma • Glioma • Heart Failure • Hematological Malignancies • Lymphoma • Meningioma • Oligodendroglioma • Oncology • Solid Tumor

In vivo evaluation of local theranostic approach to high-grade glioma with hypoxia-targeting radiopharmaceutical 64Cu-ATSM (SNMMI 2025) - "Our clinical PET study has demonstrated that Cu-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) highly accumulated in the HGGs generally expressing hypoxia marker HIF-1α... The MTD of 64Cu-ATSM local treatment in mice was 3.7 MBq. After the local treatment with MTD, Imaging and autoradiography analyses demonstrated high tumor penetration, distribution, and retention of64Cu-ATSM within HGG PDX tumors, with highly expressed hypoxic markers of HIF-1α and BNIP3. A single 64Cu-ATSM local treatment significantly prolonged overall survival as well as potently induced DNA double-strand breaks and apoptosis in tumors."

Preclinical • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • HIF1A

Phase Ⅰ Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes (SNMMI 2025) - "Radioactive Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) was initially developed for positron emission tomography (PET) imaging of tumor hypoxia... Twenty patients were enrolled, and 18 were included in the full analysis set. Among them, 9 had glioblastoma, 4 had anaplastic astrocytoma, 1 had anaplastic oligodendroglioma, 2 had malignant meningioma, and 2 had metastatic brain tumors. Intravenously administered 64Cu-ATSM was well tolerated, with an MTD of 99 MBq/kg and no serious adverse events reported."

Clinical • PK/PD data • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • Cardiovascular • CNS Disorders • Epilepsy • Glioblastoma • Glioma • Heart Failure • Hematological Malignancies • Lymphoma • Meningioma • Oligodendroglioma • Oncology • Solid Tumor

Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model. (PubMed, Acta Neuropathol Commun) - "We evaluated whether the blood-brain-barrier-permeable copper delivery drug, CuATSM, attenuated the misfolding and deposition of wild-type disSOD1 and associated neuron death in a novel mouse model that expresses this pathology...These changes were associated with a significant reduction in disSOD1 pathology and preservation of dopamine neurons in the SN, which were highly correlated with tissue copper levels. Our data position wild-type disSOD1 pathology as a novel drug target for Parkinson disease and suggest that brain copper supplementation may constitute an effective means of slowing SN dopamine neuron death in this disorder."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • SOD1

CuATSM Enhances Wound Repair Without Scarring via Hippo/YAP Signalling Pathway to Reduce Ferroptosis and Macrophage Polarisation. (PubMed, J Cell Mol Med) - "Furthermore, our findings suggest that this effect is mediated through the ferroptosis-induced Hippo/YAP signalling pathway and macrophage polarisation. These findings highlight CuATSM as a promising therapeutic candidate for achieving scarless wound repair in clinical applications."

Journal • Inflammation

CuII-bis(thioureido) Complex: A Potential Radiotracer for Detecting Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases. (PubMed, Semin Nucl Med) - "Multimodal imaging integrating PET and MRI, alongside novel structural analogs targeting Aβ plaques and redox imbalances, emerges as a strategic direction for future research. Collectively, Cu-ATSM represents a transformative tool for elucidating neuropathological mechanisms and advancing therapeutic strategies in neurodegenerative disorders."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Metabolic Disorders • Movement Disorders • Parkinson's Disease • TNFA

A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis. (PubMed, EBioMedicine) - "These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Effect of Cu(ATSM) on the expression and activity of ABC export proteins in killifish (Fundulus heteroclitus) kidney tubules. (PubMed, Environ Toxicol Pharmacol) - "Cu(ATSM)-induced activation was further suppressed by phosphatidylinositol 3-kinase inhibitor LY-294002 and mTOR inhibitor rapamycin. Activation was also inhibited by GSK650394, an inhibitor of serum-and-glucocorticoid-inducible-kinase-1 being a subsequent target. Given the parallelism with other metals, this ABC transporter regulation appears to be a general defense mechanism of teleosts to react on metallic pollutants."

Journal

Clinical characterization of IRF2BPL mutation: Case series and review of the literature. (PubMed, Medicine (Baltimore)) - "We have come across a case of recurrent seizures of epilepsy and dystonia due to a mutation in the IFR2BPL gene for which no definitive treatment has been found. Recently, several studies have led to the discovery of a new drug for the treatment of NEDAMSS. CuII (atsm) (copper II diacetylbis(4-methylaminouracil)) (CuATSM) is a small-molecular-weight drug that can be administered orally and then used in the human body. The literature suggests that the underlying mechanism of CuATSM involves the restoration of mitochondrial function, including correction of the mitochondrial differentiation and mislocalization observed in cells from NEDAMSS patients, but extensive trials are needed to demonstrate its efficacy in IFR2BPL-related diseases."

Journal • Review • CNS Disorders • Developmental Disorders • Dystonia • Epilepsy • Movement Disorders • Psychiatry • IRF2

Measurement of Airborne Radioactivity in the Inpatient Room after Administering [64Cu]Cu-ATSM to Patients (PubMed, Kaku Igaku) - "The results of this study confirmed that the airborne concentration of [64Cu]Cu-ATSM after administration to patients was below the legally permitted level."

Journal • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor

Ligand-Based Radical Reactivity of Metal Thiosemicarbazones Prompts the Identification of Platinum(II)-Based Cytoprotectants. (PubMed, J Am Chem Soc) - "CuATSM, a copper(II) complex of a bis(thiosemicarbazone) of diacetyl, prevents oxidative cell death and acts as a neuroprotectant in vivo, prompting its evaluation to treat amyotrophic lateral sclerosis and other neurodegenerative conditions in the clinic. The RTA activity determined in organic solution largely translates to phospholipid bilayers and mammalian cells, where most complexes inhibited lipid peroxidation and associated ferroptotic cell death. A preliminary structure-activity study revealed Pt complexes with potencies eclipsing those of archetype ferroptosis inhibitors ferrostatin-1 and liproxstatin-1, suggesting that Pt (and to a lesser extent Ni) bis(thiosemicarbazone)s may be better suited to optimization for therapeutic development than those based on Cu."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Additive Effects of Cu-ATSM and Radiation on Survival of Diffuse Intrinsic Pontine Glioma Cells. (PubMed, Radiat Res) - "Cu-ATSM toxicity in DIPG cells was also inhibited by overexpression of mitochondrial-targeted catalase. These results support the hypothesis that Cu-ATSM is selectively cytotoxic to DIPGs by a mechanism involving H2O2 generation and copper and being additively cytotoxic with ionizing radiation."

Journal • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • CAT

Evaluations for quality management of metal impurities in [64Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]Cu-ATSM) as a radiopharmaceutical (EANM 2024) - "This study showed that trace amounts of Ni2+, Fe2+, and Zn2+ had little effect on the quality of [64Cu] Cu-ATSM. However, it was concluded that the concentration of Cu2+ should be controlled. These results would provide useful information for the quality management of [64Cu]Cu-ATSM."

Brain Cancer • Oncology • Solid Tumor

Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis. (PubMed, Neurotherapeutics) - "Treatment of EAE mice with the CNS-permeant copper modulating compound CuII(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with CuII(atsm) showing initial promise."

Journal • CNS Disorders • Immunology • Multiple Sclerosis

Phase I clinical trial of 64 Cu-ATSM for malignant brain tumors. (ASCO 2024) - "Intravenous administration of 64 Cu-ATSM was feasible and well tolerated in patients with malignant brain tumors. The recommended dose for future trials is 99 MBq/kg. The initial efficacy outcomes obtained in this study warrant more clinical evaluation of this new treatment approach for brain tumors with no currently available treatment options."

Clinical • P1 data • Brain Cancer • CNS Lymphoma • Glioblastoma • Glioma • Hematological Disorders • Hematological Malignancies • Lymphoma • Meningioma • Oncology • Solid Tumor

Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS. (PubMed, Sci Rep) - "Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Patient-Derived Blood-Brain Barrier Model for Screening Copper Bis(thiosemicarbazone) Complexes as Potential Therapeutics in Alzheimer's Disease. (PubMed, ACS Chem Neurosci) - "To demonstrate its utility as a small molecule drug candidate screening platform, we investigated the effects of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(atsm)) and a library of metal bis(thiosemicarbazone) complexes─a class of compounds exhibiting antineuroinflammatory therapeutic potential in neurodegenerative disorders...Together, the presented model provides an effective and easily scalable in vitro BBB platform for screening AD drug candidates. Its improved translational potential makes it a valuable tool for advancing the development of metal-based compounds aimed at modulating neuroinflammation in AD."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • IFNG • TNFA