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Salirasib (known also as S-Farnesylthiosalicylic acid; Farnesyl Thiosalicylic Acid; FTS), a salicylic acid analog, is a potent and competitive prenylated protein methyltransferase (PPMTase) inhibitor with potential antineoplastic activity. At 2.6 microM, it suppresses Ras methylation. A third of human cancers, including those of the breast, colon, lung, and pancreas, are thought to be abnormally activated RAS signaling cascades that are linked to cell senescence, differentiation, and proliferation. Salirasib inhibits all Ras isoforms from their membrane-anchoring sites, preventing activation of these cascades.
Physicochemical Properties
| Molecular Formula | C22H30O2S | |
| Molecular Weight | 358.54 | |
| Exact Mass | 358.196 | |
| Elemental Analysis | C, 73.70; H, 8.43; O, 8.92; S, 8.94 | |
| CAS # | 162520-00-5 | |
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| PubChem CID | 5469318 | |
| Appearance | White to light yellow solid powder | |
| Density | 1.1±0.1 g/cm3 | |
| Boiling Point | 486.0±45.0 °C at 760 mmHg | |
| Melting Point | 64-66°C | |
| Flash Point | 247.7±28.7 °C | |
| Vapour Pressure | 0.0±1.3 mmHg at 25°C | |
| Index of Refraction | 1.559 | |
| LogP | 8.53 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 10 | |
| Heavy Atom Count | 25 | |
| Complexity | 498 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | S(C1=C([H])C([H])=C([H])C([H])=C1C(=O)O[H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])[H] |
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| InChi Key | WUILNKCFCLNXOK-CFBAGHHKSA-N | |
| InChi Code | InChI=1S/C22H30O2S/c1-17(2)9-7-10-18(3)11-8-12-19(4)15-16-25-21-14-6-5-13-20(21)22(23)24/h5-6,9,11,13-15H,7-8,10,12,16H2,1-4H3,(H,23,24)/b18-11+,19-15+ | |
| Chemical Name | 2-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl]sulfanylbenzoic acid | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | RAS; PPMTase (Ki = 2.6 μM) | |
| ln Vitro |
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| ln Vivo |
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| Enzyme Assay | For methyltransferase assays in cell-free systems, total membranes of cultured cell lines (100,000 × g pellet) or synaptosomal membranes of the rat brain cerebellum are utilized. 50 μL of 50 mM Tris-HCl buffer, pH 7.4, 100 μg of protein, 25 μM [methyl-3H]AdoMet (300,000 cpm/nmol), and 50 μM AFC (prepared as a stock solution in DMSO) are used in methyltransferase assays. The assays are conducted at 37°C. 8% DMSO is used in all of the assays. As stated in the text, different AFC concentrations are used in a number of experiments. After 10 minutes, the reactions are stopped by adding 500 μL of a 1:1 chloroform:methanol mixture, followed by mixing and phase separation, and 250 μL of H2O. A 200 μl solution of 1 N NaOH and 1% SDS is added to a 125-μL portion of the chloroform phase that has been dried at 40°C. The vapor phase equilibrium method is used to count the methanol that is thus formed. When AFC is added, typical background counts (without AFC) range from 50 to 100 cpm, while typical reactions yield 500 to 6,000 cpm. Three duplicates of each assay are run, and background counts are deducted. Gel electrophoresis and methylation of endogenous substrates are carried out. In intact cells, protein carboxyl methylation is measured with 100 μCi/mL [methyl-3H]methionine. Nearly confluent cultures of the cells are cultivated in 10-cm plates with 5 mL of labeling medium before analysis. | |
| Cell Assay | Cells are harvested using 0.05% Trypsin-EDTA every day for one to seven days in time-dependent response studies. The Trypan blue exclusion method is then used under a microscope to count the cells. Cells are cultured in medium supplemented with salirasib or DMSO for three days in order to conduct dose response studies. As directed by the manufacturer, a colorimetric WST-1 assay is used to assess cell viability. Using GraphPad Prism software, nonlinear regression analysis is used to determine the IC50 value, or the point at which 50% of the cell growth is inhibited when compared to the DMSO control. | |
| Animal Protocol | Female athymic NMRI nu/nu mice, aged six weeks, are kept in cages with filters on top and are given unlimited access to food and drink. Twelve mice receive a subcutaneous injection of 5x106 HepG2 cells suspended in 100 μL PBS to create tumors in their right lower flank. When palpable tumors have developed two weeks after cell inoculation, mice are divided into two groups: one for salirasib treatment (n = 6) and the other for control (n = 4). Two of the animals had to be removed from the study because they do not develop tumors at that point. For 12 days, they are given daily intraperitoneal injections (10 mg/kg salirasib) or an equivalent volume of vehicle solution (PBS with 2.5% v/v ethanol, pH 8.0). A digital calliper is used to record tumor dimensions three times a week beginning on the first day of treatment. To estimate tumor volumes, use the formula V (mm3)=(length×width2)/2. To assess the effectiveness of treatment, tumour weights are noted at the moment of sacrifice. | |
| References |
[1]. Farnesylthiosalicylic acid (salirasib) inhibits Rheb in TSC2-null ELT3 cells: a potential treatment for lymphangioleiomyomatosis. Int J Cancer. 2012 Mar 15;130(6):1420-9. [2]. The Ras antagonist, farnesylthiosalicylic acid (FTS), decreases fibrosis and improves muscle strength in dy/dy mouse model of muscular dystrophy. PLoS One. 2011 Mar 22;6(3):e18049. [3]. Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor growth in vivo through ras and mTOR inhibition. Mol Cancer. 2010 Sep 22;9:256. |
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| Additional Infomation |
Salirasib is a sesquiterpenoid. Salirasib has been used in trials studying the diagnostic of Carcinoma, Non-Small-Cell Lung. Salirasib is a salicylic acid derivative with potential antineoplastic activity. Salirasib dislodges all Ras isoforms from their membrane-anchoring sites, thereby preventing activation of RAS signaling cascades that mediated cell proliferation, differentiation, and senescence. RAS signaling is believed to be abnormally activated in one-third of human cancers, including cancers of the pancreas, colon, lung and breast. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.97 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. Solubility in Formulation 2: 2.5 mg/mL (6.97 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7891 mL | 13.9454 mL | 27.8909 mL | |
| 5 mM | 0.5578 mL | 2.7891 mL | 5.5782 mL | |
| 10 mM | 0.2789 mL | 1.3945 mL | 2.7891 mL |