Delving into the Latest Updates on Cu(II)ATSM with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Copper(II)-diacetyl-di(N4-methylthiosemicarbazone), Cu-ATSM, Cu-diacetyl-bis(N4-methylthiosemicarbazonate)

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Target-

Mechanism

Neurons modulators

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic DiseaseOther Diseases

Active Indication-

Inactive Indication

Amyotrophic Lateral SclerosisParkinson Disease

Originator Organization

University of Melbourne

Active Organization-

Inactive Organization

Collaborative Medicinal Development LLC

Drug Highest PhasePendingPhase 3

First Approval Date-

Regulation-

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Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive and treatment-resistant childhood primary brainstem tumors with a median survival of less than one year after diagnosis. The prevailing standard of care for DIPG, radiation therapy, does not prevent fatal disease progression, with most patients succumbing to this disease 3–8 months after completion of radiation therapy. This underscores the urgent need for novel combined-modality approaches for enhancing therapy responses. This study demonstrates that the cellular redox modulating drug, copper (II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) dose-dependently (1–3 μM) decreased clonogenic cell survival in SU-DIPG50 and SU-DIPG36 cell lines during 6 h of exposure but had no significant effect on survival in normal human astrocytes (NHA). Additional significant (>90%) decreases in DIPG clonogenic survival were observed at 24 h of Cu-ATSM exposure. However, NHAs also began to show dose-dependent 10–70% survival decreases at this point. Notably, 3 μM Cu-ATSM for 6 h resulted in additive clonogenic cell killing of DIPG lines when combined with radiation, which was not seen in NHAs and was partially inhibited by the copper chelator, bathocuproinedisulfonic acid. 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.

01 Oct 2023·American Journal of Physiology-Lung Cellular and Molecular Physiology

IL-17A neutralization fails to attenuate airway remodeling and potentiates a proinflammatory lung microenvironment in diacetyl-exposed rats

Article

Author: Chalupa, David ; Johnston, Carl J. ; House, Emma L. ; Hernady, Eric ; McGraw, Matthew D. ; Groves, Angela M. ; Kim, So-Young

Interleukin-17A (IL-17A) neutralization has shown benefit previously in preclinical models of transplant-associated bronchiolitis obliterans (BO), yet it remains unknown whether IL-17A neutralization has similar benefit for other forms of BO. Here, IL-17A neutralization fails to prevent severe airway remodeling in rats exposed repetitively to the flavoring chemical diacetyl, and instead, promotes a proinflammatory microenvironment with increased expression of TNF-α, IL-1β, and NF-κB within the lung.

10 May 2023·Diagnostics (Basel, Switzerland)

Feasibility of Renal Blood Flow Measurement Using ⁶⁴Cu-ATSM PET/MRI: A Quantitative PET and MRI Study.

Article

Author: Iwano, Masayuki ; Takahashi, Naoki ; Mori, Tetsuya ; Tsujikawa, Tetsuya ; Okazawa, Hidehiko ; Nishikawa, Yudai ; Kiyono, Yasushi ; Kimura, Hideki ; Kobayashi, Mamiko ; Nishimori, Kazuhisa ; Nishikawa, Sho ; Kasuno, Kenji ; Shimamoto, Yuki

This study aimed to evaluate the renal blood flow (RBF) in patients with chronic kidney disease (CKD) using ⁶⁴Cu(II)-diacetyl-bis(4-methylthiosemicarbazonate) (⁶⁴Cu-ATSM) for positron emission tomography (PET)/magnetic resonance imaging (MRI). We included five healthy controls (HCs) and ten patients with CKD. The estimated glomerular filtration rate (eGFR) was calculated from the serum creatinine (cr) and cystatin C (cys) levels. The estimated RBF (eRBF) was calculated using the eGFR, hematocrit, and filtration fraction. A single dose of ⁶⁴Cu-ATSM (300-400 MBq) was administered for RBF evaluation, and a 40 min dynamic PET scan was performed with simultaneous arterial spin labeling (ASL) imaging. PET-RBF images were obtained from the dynamic PET images at 3 min after injection using the image-derived input function method. The mean eRBF values calculated from various eGFR values differed significantly between the patients and HCs; both groups also differed significantly in terms of the RBF values (mL/min/100 g) measured using PET (151 ± 20 vs. 124 ± 22, p < 0.05) and ASL-MRI (172 ± 38 vs. 125 ± 30, p < 0.001). The ASL-MRI-RBF was positively correlated with the eRBFcr-cys (r = 0.858, p < 0.001). The PET-RBF was positively correlated with the eRBFcr-cys (r = 0.893, p < 0.001). The ASL-RBF was positively correlated with the PET-RBF (r = 0.849, p < 0.001). ⁶⁴Cu-ATSM PET/MRI demonstrated the reliability of PET-RBF and ASL-RBF by comparing them with eRBF. This is the first study to demonstrate that ⁶⁴Cu-ATSM-PET is useful for assessing the RBF and is well correlated with ASL-MRI.

100 Deals associated with Cu(II)ATSM

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Amyotrophic Lateral Sclerosis	Phase 3	AU	Collaborative Medicinal Development LLC	30 Sep 2019
Parkinson Disease	Phase 3	AU	Collaborative Medicinal Development LLC	14 Aug 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


CMD-2016-001 \| CuATSM (AAN2020)	Phase 2	Amyotrophic Lateral Sclerosis	15	CuATSM	amajmzhkzv(ptyihhfivz) = mvuiylhdkz meszjtrpri (etprmcizaz )	Positive	14 Apr 2020