PX-12 has an IC50 of 1.9 μM for MCF-7 cells and 2.9 μM for HT-29 cells, respectively, which inhibits their growth[1]. By thio-alkylating the key cysteine residue (Cys73), which is situated outside of Trx-1's conserved redox catalytic region, PX-12 specifically lowers the activity of Trx-1. PX-12 influences several cell surface proteins' thiol oxidation status. Important surface receptors involved in platelet adhesion and activation are impacted, such as the von Willebrand factor receptor (GPIb) and the collagen receptor (GPVI). In whole blood, PX-12 prevents thrombus formation over Type I collagen when flow conditions are met[2]. Cellular redox protein thioredoxin-1 (Trx-1) up-regulates vascular endothelial growth factor and hypoxia-inducible factor-1α, suppresses apoptosis, and encourages the growth of tumors[3]. PX-12 has a dose- and time-dependent effect on the proliferation of colorectal cancer DLD-1 and SW620 cells. PX-12 inhibits the growth of new cell colonies and causes a G2/M phase arrest in the cell cycle. Treatment with PX-12 causes apoptosis. PX-12 prevents colon cancer cells from migrating and invading. PX-12 treatment enhances KLF17 mRNA expression while decreasing NOX1, CDH17, and S100A4 mRNA expression in cancer cells. In colorectal cancer cells, PX-12 reduces the expression of the S100A4 protein[4].

PX-12 has been evaluated in a phase I clinical trial including patients and has demonstrated in vivo anticancer efficacy against human tumor xenografts, including HT-29 colon cancer in SCID mice[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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.28 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 2: ≥ 2.5 mg/mL (13.28 mM) (saturation unknown) in 10% EtOH + 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 EtOH 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 3: ≥ 2.5 mg/mL (13.28 mM) (saturation unknown) in 10% EtOH + 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 EtOH 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 4: (saturation unknown) in (add these co-solvents sequentially from left to right, and one by one),

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