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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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.

01 Feb 2023·Cell Death & Differentiation

Ferroptotic stress facilitates smooth muscle cell dedifferentiation in arterial remodelling by disrupting mitochondrial homeostasis

Article

Author: Zhang, Guo-Yan ; Zhang, Jia-Bao ; Wang, Xu-Jie ; Zhang, Zhen ; Wang, Pei ; Lu, Jin-Jian ; Wu, Wen-Bin ; Sun, Di-Yang ; Li, Dong-Jie ; Tong, Jie ; Zeng, Fei-Yan ; Ji, Qing-Xin ; Shen, Fu-Ming ; Zhou, Jian ; Cao, Wen-Xiang

Smooth muscle cell (SMC) phenotypic switch from a quiescent 'contractile' phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bis^N4-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.

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	ximatbbddt(ujgoarsmzo) = uhnypsbehc tyqbmntoyn (xujkjxruko )	Positive	14 Apr 2020