Elesclomol (STA-4783)   中文名称: 伊利司莫

Copper-dependent cell death (cuproptosis)

FDX1 的 α2/α3 螺旋和 β5 链与 elisclomol (STA-4783) 结合，但不与旁系同源蛋白 FDX2 结合。一种新型 FDX1 底物是 esclomol-Cu(II)。 Elesclomol-Cu(II) 复合物与 FDX1 蛋白结合并被 FDX1 蛋白还原 [1]。仅两小时后，电解溶酶-Cu（1:1 比例）(40 nM) 可使细胞内铜水平增加 15-60 倍，导致 ABC1 细胞在 24 小时内死亡 [1]。治疗前，以 1:1 摩尔比将铜添加到艾司洛醇中会显着降低糖酵解（葡萄糖培养基）培养物中生长的细胞的活力 [2]。用艾司氯醇（200 nM；18 小时）处理的 HSB2 细胞有更多的早期和晚期凋亡细胞。艾司洛醇会引起氧化应激，从而导致癌细胞凋亡[3]。 Elesclomol 的 IC50 值分别为 110 nM、24 nM 和 9 nM，可显着降低 SK-MEL-5、MCF-7 和 HL-60 细胞的活力 [5]。

Elesclomol（10 mg/kg；皮下注射；从产后第 5 天至第 26 天每三天一次，每周直至产后第 54 天）治疗可改善肥厚性心脏病并部分减少严重心脏病。接受 Elesclomol 后，心脏 [Cu] 从载体敲除水平的 34% 上升至 55% [4]。 Elesclomol 会增加大脑中细胞色素 C 氧化酶的含量，并将铜转运至线粒体。在斑点小鼠中，Elesclomol可提高存活率并避免有害的神经系统改变 [4]。

细胞凋亡分析[3]
细胞类型： HSB2 细胞
测试浓度： 200 nM
孵育时间： 18 小时
实验结果：早期和晚期凋亡细胞的数量增加。

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

128.86

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.24 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.24 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: 1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL

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配方 4 中的溶解度: 5 mg/mL (12.48 mM) in 50% PEG300 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。