Tetrathiomolybdate (0.2 mg/mouse/day; oral; 10 weeks) has a prophylactic and shielding effect on mice that have arthritis caused by collagen[1]. Tetrathiomolybdate (0.03 mg/mL; given to water, 8 weeks) reduces erythema and swelling to prevent collagen-induced arthritis in mice from progressing[1].

Animal/Disease Models: Collagen-induced arthritis model in mice[1]
Doses: 0.2 mg/mouse/day or 0.03 mg/mL, added in water
Route of Administration: Oral gavage, for 10 weeks; Collagen injected at weeks 2
Experimental Results: demonstrated significant preventive effect and protective effect in mice.

[1]. Tetrathiomolybdate is partially protective against hyperglycemia in rodent models of diabetes. Exp Biol Med (Maywood). 2008 Aug;233(8):1021-5.

Tetrathiomolybdate (2-) is a molybdenum coordination compound that acts as a copper chelator. Tetrathiomolybdate is an orally administered small-molecule anticopper agent that highly specifically reduces serum free copper levels. COPREXA has completed pivotal clinical trials for the treatment of Wilson's disease of the nervous system. It is also being developed for the treatment of fibrotic diseases, based on the premise that the progression of fibrotic diseases depends on the availability of free copper in the body. Tetrathiomolybdate is an orally bioavailable copper (Cu) chelator with potential anti-angiogenic, anti-metastatic, and antitumor activities. After oral administration, Tetrathiomolybdate (TM) targets and binds to copper and food proteins in the gastrointestinal tract, forming a stable complex that prevents copper absorption and reabsorption. Furthermore, absorbed free TM targets and binds to copper in the blood and serum albumin. This depletes systemic copper reserves, leading to copper deficiency in the tumor microenvironment (TME). TM chelates copper and downregulates the expression of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), for which copper is a cofactor, and inhibits the production of nuclear factor-κB (NF-κB). Copper deficiency also inhibits the activity and levels of copper-dependent angiogenic enzymes such as vascular endothelial growth factor receptor (VEGFR). This modulates the activity of VEGFR-positive endothelial progenitor cells (EPCs), which are essential for metastasis. EPC deficiency leads to inhibited angiogenesis, thereby preventing metastasis. TM also inhibits the activity of other copper-containing metalloenzymes, including superoxide dismutase 1 (SOD1), cytochrome C oxidase, vascular adhesion protein-1 (VAP-1), antioxidant protein 1 copper chaperone (ATOX-1), and matrix metalloproteinase 9 (MMP-9) in endothelial cells. Inhibition of these enzymes interferes with the activation of multiple signal transduction pathways required for cell proliferation and angiogenesis. TM also inhibits the activity and level of lysyl oxidase-like protein 2 (LOXL2; lysyl oxidase homolog 2), a copper-dependent amine oxidase crucial for constructing the pre-metastatic microenvironment and promoting metastasis, tumor cell migration, and invasion. Furthermore, copper depletion attenuates the activation of host cells (including cancer-associated fibroblasts (CAFs)) in the tumor microenvironment, modulates tumor-associated macrophages (TAMs), and promotes cytotoxic T lymphocyte (CTL)-mediated anti-tumor immune responses.

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Drug Indications
It has been investigated for the treatment of liver disease and pulmonary fibrosis.

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Mechanism of Action
Tetrathiomolybdate has been demonstrated in several established animal models to inhibit fibrosis by chelating available copper and inhibiting key fibrotic cytokines, including cysteine-rich secretory protein acid (SPARC), NF-κB, TGF-β, FGF-2, IL-1, IL-6, IL-8, and connective tissue growth factor (CTGF).

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Pharmacodynamics
Tetrathiomolybdate can reduce toxic free copper levels and significantly improve the clinical neurological prognosis of patients with Wilson's disease. Studies have also shown that it can specifically inhibit the progression of chronic pulmonary fibrosis.

MOS42-

224.22

225.794

16330-92-0

Ammonium tetrathiomolybdate(VI);15060-55-6

5245480

Typically exists as solid at room temperature

1.291

2

4

0

5

19.1

0

S=[Mo]([S-])(=S)[S-]

VVRHUOPINLMZBL-UHFFFAOYSA-L

InChI=1S/Mo.2H2S.2S/h;2*1H2;;/p-2

bis(sulfanylidene)molybdenum;sulfanide

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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