Copper-dependent cell death (cuproptosis)

FDX1's α2/α3 helix and β5 strand are bound by elisclomol (STA-4783), but not by the paralogous protein FDX2. A novel FDX1 substrate is elesclomol-Cu(II). Elesclomol-Cu(II) complex is bound by and reduced by the FDX1 protein [1]. After just two hours, electrolysomol-Cu (1:1 ratio) (40 nM) increases intracellular copper levels by 15–60 times, leading to the death of ABC1 cells within 24 hours [1]. Prior to treatment, adding copper to elesclomol at a 1:1 molar ratio dramatically lowers cell viability in cells grown in glycolytic (glucose media) culture [2]. HSB2 cells treated with esclomol (200 nM; 18 hours) have more early and late apoptotic cells. Elesclomol causes oxidative stress, which causes cancer cells to undergo apoptosis [3]. Elesclomol, with IC50 values of 110 nM, 24 nM, and 9 nM, respectively, dramatically reduces the viability of SK-MEL-5, MCF-7, and HL-60 cells [5].

Elesclomol (10 mg/kg; subcutaneous; every three days from postpartum day 5 to 26 and weekly till postpartum day 54) treatment improved hypertrophic heart disease and partially decreased severe cardiac pathology. After receiving Elesclomol, heart [Cu] rose from 34% to 55% of vector knockout levels [4]. Elesclomol raises the amounts of cytochrome c oxidase in the brain and transports copper to the mitochondria. In spotted mice, eloxamol enhances survival and averts detrimental neurological alterations [4].

Apoptosis Analysis[3]
Cell Types: HSB2 cells
Tested Concentrations: 200 nM
Incubation Duration: 18 hrs (hours)
Experimental Results: Increased the number of early and late apoptotic cells.

Animal/Disease Models: Cardiac Ctr1 knockout mice[4]
Doses: 10 mg/kg
Route of Administration: subcutaneous (sc) injection; every three days from post-natal day 5 to 26 and once weekly until post-natal day 54
Experimental Results: Ameliorated severe cardiac pathology with a partial reduction in hypertrophy.

[1]. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022 Mar 18;375(6586):1254-1261.

[2]. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol. 2019 Jul;15(7):681-689.

[3]. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther. 2008 Aug;7(8):2319-27.

[4]. Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice. Science. 2020 May 8;368(6491):620-625.

[5]. Chemistry and biology of deoxynyboquinone, a potent inducer of cancer cell death. J Am Chem Soc. 2010 Apr 21;132(15):5469-7.

Elesclomol is a carbohydrazide obtained by formal condensation of the carboxy groups of malonic acid with the hydrino groups of two molar equivalents of N-methylbenzenecarbothiohydrazide It has a role as an antineoplastic agent and an apoptosis inducer. It is a carbohydrazide and a thiocarbonyl compound. It is functionally related to a malonic acid.
Elesclomol is a novel, injectable, drug candidate that kills cancer cells by elevating oxidative stress levels beyond a breaking point, triggering programmed cell death. In preclinical models elesclomol showed potent killing of a broad range of cancer cell types at high doses, and an ability to strongly enhance the efficacy of certain chemotherapy agents, with minimal additional toxicity, at moderate doses. It is being developed by Synta Pharmaceuticals.
Elesclomol is a small-molecule bis(thio-hydrazide amide) with oxidative stress induction, pro-apoptotic, and potential antineoplastic activities. Elesclomol induces oxidative stress, creating high levels of reactive oxygen species (ROS), such as hydrogen peroxide, in both cancer cells and normal cells. Because tumor cells have elevated levels of ROS compared to normal cells, the increase in oxidative stress beyond baseline levels elevates ROS beyond sustainable levels, exhausting tumor cell antioxidant capacity, which may result in the induction of the mitochondrial apoptosis pathway. Normal cells are spared because the increase in the level of oxidative stress induced by this agent is below the threshold at which apoptosis is induced.

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Drug Indication
Investigated for use/treatment in melanoma.

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Mechanism of Action
Elesclomol acts through a novel mechanism of action. Elesclomol has been shown to rapidly cause a dramatic increase in oxidative stress (ROS) inside cancer cells. The prolonged elevation of ROS inside cancer cells induced by elesclomol causes the cell to exceed a critical breaking point and undergo apoptosis. The triggering of the mitochondrial apoptosis pathway is observed within the first six hours of applying elesclomol. Cancer cells operate at a much higher intrinsic level of ROS than normal cells, and have a greatly reduced anti-oxidant capacity compared to normal cells. This leaves them more vulnerable to an agent such as elesclomol that elevates oxidative stress. In similar experiments at similar doses, elesclomol has been found to have little to no impact on normal cells.

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Pharmacodynamics
Elesclomol is a first-in-class heat shock protein 70 (Hsp70) inducer that activates natural killer (NK) cell-mediated tumor killing.

C19H20N4O2S2

400.5

400.102

C, 56.98; H, 5.03; N, 13.99; O, 7.99; S, 16.01

488832-69-5

300471

Light yellow to yellow solid powder

1.3±0.1 g/cm3

1.668

1.98

2

4

4

27

510

0

BKJIXTWSNXCKJH-UHFFFAOYSA-N

InChI=1S/C19H20N4O2S2/c1-22(18(26)14-9-5-3-6-10-14)20-16(24)13-17(25)21-23(2)19(27)15-11-7-4-8-12-15/h3-12H,13H2,1-2H3,(H,20,24)(H,21,25)

N'1,N'3-dimethyl-N'1,N'3-di(phenylcarbonothioyl)malonohydrazide

STA 4783, Elesclomol; STA4783; STA-4783; Elesclomol (STA-4783); STA4783; N'1,N'3-dimethyl-N'1,N'3-di(phenylcarbonothioyl)malonohydrazide; Elesclomol [USAN]

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL

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Solubility in Formulation 4: 5 mg/mL (12.48 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)