Decuprate (bis-choline tetrathiomolybdate)

Inhibiting the glutathione system induces ferroptosis, a non-apoptotic form of cell death driven by lipid peroxidation, with compounds like withaferin A and altretamine showing strong preclinical activity...Trx reductase inhibition by auranofin or mitomycin C further destabilizes redox balance, promoting mitochondrial dysfunction and apoptosis. SOD1 inhibitors, including ATN-224 and disulfiram, selectively enhance oxidative stress in tumor cells and are currently being tested in clinical trials. Mounting preclinical and clinical evidence supports redox modulation as a cancer-selective vulnerability. Pharmacologically tipping the redox balance beyond the threshold of cellular tolerance offers a rational and potentially powerful approach to eliminate malignant cells while sparing healthy tissue, highlighting novel strategies for targeted cancer therapy at the interface of redox biology and oncology.

Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.

P3, N=214, Terminated, Alexion Pharmaceuticals, Inc. | Trial primary completion date: Feb 2021 --> Jun 2023

Objective An ongoing phase 3 study (NCT03403205) will assess the efficacy and safety of ALXN1840, a novel copper-binding agent in patients with WD...The most common neurological manifestations, defined as an abnormal UWDRS III score >0, at baseline in Cohort 1 were impaired speech (43.1%), finger taps (41.9%), rapid alternating hand movements (39.4%) and postural arm tremor (38.9%) and in Cohort 2 were postural arm tremor (48.9%), salivation (38.3%), wing-beating tremor (36.1%) and impaired speech (34.0%). Conclusions Tremor and speech disturbances are among the most common neurological symptoms in patients with WD in these cohorts.