PX-12

PX-12 对于 MCF-7 细胞和 HT-29 细胞的 IC50 分别为 1.9 μM 和 2.9 μM，抑制其生长[1]。通过硫代烷基化位于 Trx-1 保守氧化还原催化区域之外的关键半胱氨酸残基 (Cys73)，PX-12 特异性降低 Trx-1 的活性。 PX-12 影响多种细胞表面蛋白的硫醇氧化状态。参与血小板粘附和活化的重要表面受体受到影响，例如冯维勒布兰德因子受体 (GPIb) 和胶原蛋白受体 (GPVI)。在全血中，当满足流动条件时，PX-12 可防止 I 型胶原上形成血栓[2]。细胞氧化还原蛋白硫氧还蛋白-1（Trx-1）上调血管内皮生长因子和缺氧诱导因子-1α，抑制细胞凋亡，促进肿瘤生长[3]。 PX-12 对结直肠癌 DLD-1 和 SW620 细胞的增殖具有剂量和时间依赖性影响。 PX-12 抑制新细胞集落的生长并导致细胞周期停滞在 G2/M 期。 PX-12 处理会导致细胞凋亡。 PX-12 可防止结肠癌细胞迁移和侵袭。 PX-12 治疗可增强癌细胞中 KLF17 mRNA 的表达，同时降低 NOX1、CDH17 和 S100A4 mRNA 的表达。在结直肠癌细胞中，PX-12 降低 S100A4 蛋白的表达[4]。

PX-12 已在包括患者在内的 I 期临床试验中进行了评估，并证明了对人类肿瘤异种移植物（包括 SCID 小鼠中的 HT-29 结肠癌）的体内抗癌功效[3]。

Absorption, Distribution and Excretion
the optimum PD dose was identified as 96 mg/m2 as a 3-hr infusion

[1]. The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. Mol Cancer Ther. 2003 Mar;2(3):235-43.

[2]. Physical interaction between human ribonucleotide reductase large subunit and thioredoxin increases colorectal cancer malignancy. J Biol Chem. 2017 Jun 2;292(22):9136-9149.

[3]. Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation. PLoS One. 2016 Oct 7;11(10):e0163006.

[4]. A Phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors. Clin Cancer Res. 2007 Apr 1;13(7):2109-14.

[5]. Thioredoxin-1 inhibitor, 1-methylpropyl 2-imidazolyl disulfide, inhibits the growth, migration and invasion of colorectal cancer cell lines. Oncol Rep. 2015 Feb;33(2):967-73.

2-(butan-2-yldisulfanyl)-1H-imidazole is a member of imidazoles.
PX-12 (1-methylpropyl 2-imidazolyl disulfide) is a small-molecule inhibitor of Trx-1 (thioredoxin-1), stimulates apoptosis, down-regulates HIF-1α and vascular endothelial growth factor (VEGF) and inhibits tumor growth in animal models. Since high levels of Trx-1 have been associated with colorectal, gastric and lung cancers, PX-12 is indicated as a potential cancer treatment in combination with chemotherapy for patients with advanced metastatic cancer. Initial trials correlated doses of Px-12 with increased patient survival.
Thioredoxin-1 Inhibitor PX-12 is an orally bioavailable small molecule with potential antineoplastic activity. Thioredoxin-1 inhibitor PX-12 irreversibly binds to thioredoxin-1 (Trx-1) and inhibits its activity, which may result in growth inhibition and the induction of apoptosis. Overexpressed in many cancer cell types, the low molecular weight redox protein Trx-1 regulates transcription factor activity and inhibits apoptosis, promoting cell growth and survival; it also interacts with growth factors extracellularly to stimulate cell growth.

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Drug Indication
Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, and pancreatic cancer.

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Mechanism of Action
PX-12 irreversibly inhibits the redox protein thioredoxin, which has been associated with cancer and tumor growth.

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Pharmacodynamics
PX-12 is a small molecule irreversible inhibitor of the redox protein thioredoxin. Thioredoxin is involved in the first unique step in DNA synthesis. Thioredoxin also provides control over a number of transcription factors affecting cell proliferation and death through the mechanism of redox regulation Trx regulates cell growth through the following steps: 1) Trx is reduced into its active state, Trx (red) by the enzyme thioredoxin reductase. 2) Trx enters the nucleus to regulate transcription factor activity (factors which affect DNA replication). 3) Trx is excreted out of cell where it works with other growth factors (GF) to stimulate cell growth. It has been shown that many cancer cells secrete thioredoxin; increased levels of thioredoxin protein have been reported in a wide range of human cancers including hepatoma, lung, squamous cervical carcinoma, primary gastric cancers, and colorectal carcinomas;thioredoxin stimulates the growth of a wide variety of human leukemia and solid tumor cell lines; thioredoxin, when it is over-produced, transforms normal cells into cancer cells; thioredoxin is a potent inhibitor of apoptosis and provides a survival as well as a growth advantage to tumors; elevated tumor thioredoxin levels have been associated with decreased patient survival in colon cancer and NSCLC; and elevated thioredoxin levels cause a decrease in sensitivity of cells to cancer drugs such as doxorubicin (14 fold), vincristine (8 fold), cisplatin (5 fold), and cytosine arabinoside (13 fold). Therefore PX-12, by limiting the over-expression of thioredoxin in human tumors, could reduce resistance to chemotherapy.

C7H12N2S2

188.3136

188.044

141400-58-0

219104

White to light yellow solid powder

2.3

79.3

1

3

4

11

111

0

S(C([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])SC1=NC([H])=C([H])N1[H]

BPBPYQWMFCTCNG-UHFFFAOYSA-N

InChI=1S/C7H12N2S2/c1-3-6(2)10-11-7-8-4-5-9-7/h4-6H,3H2,1-2H3,(H,8,9)

2-(sec-butyldisulfanyl)-1H-imidazole.

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 (13.28 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 2 中的溶解度: ≥ 2.5 mg/mL (13.28 mM) (饱和度未知) in 10% EtOH + 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 澄清乙醇储备液加入到 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 3 中的溶解度: ≥ 2.5 mg/mL (13.28 mM) (饱和度未知) in 10% EtOH + 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，将 100 μL 25.0 mg/mL 澄清乙醇储备液加入 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 4 中的溶解度: (饱和度未知) in (这些助溶剂从左到右依次添加，逐一添加),

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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。