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| Targets |
Inolitazone targets the peroxisome proliferator-activated receptor gamma (PPARγ). It is a high-affinity agonist of PPARγ, with an EC50 that is one-fiftieth that of rosiglitazone. By activating PPARγ, it regulates the transcription of genes involved in cell growth, differentiation, and metabolism. Its growth inhibitory effects are mediated through a PPARγ-dependent mechanism.
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| ln Vitro |
Inolitazone (RS5444) increases the expression of p21 WAF1/CIP1, a cell cycle kinase inhibitor. When p21 WAF1/CIP1 is silenced, cells become resistant to inolitazone. Using a PPRE response element coupled to a luciferase reporter (PPRE3-tk-luc), a transient transfection test shows that inolitazone at a concentration of 10 nM activates PPARγ:RXRα-dependent transcription. The appropriate concentrations of Inolitazone, Rosiglitazone, or Troglitazone were applied to DRO cells in culture. PPRE3-tk-luc was transiently transfected into DRO cells in order to measure the effective concentration at which EC50 is reached. Inolitazone's EC50 is 1 nM, rosiglitazone's is 65 nM, and troglitazone's is 631 nM. Likewise, 0.8 nM for Inolitazone, 75 nM for Rosiglitazone, and 1412 nM for Troglitazone were determined to have the IC50 inhibitory values. PPARγ is selectively activated by inolitazone, but PPARα and PPARδ are not. After transient transfection with the relevant PPAR isoform (γ, α, or δ) and a PPAR response element connected to a luciferase reporter gene, a 10 nM Inolitazone alone was applied in the presence of PPARγ and PPRE3-tk-luc in a RIE rat intestinal cell line that does not express PPAR [1]. DRO cell proliferation is inhibited by 10 nM Inolitazone (RS5444) via a PPARγ-dependent mechanism [2].
Inolitazone inhibits the growth of DRO cells through a PPARγ-dependent mechanism at a concentration of 10 nM. It upregulates the cell cycle kinase inhibitor p21WAF1/CIP1. It activates PPARγ:RXRα-dependent transcription using a luciferase reporter gene fused to a PPRE response element (PPRE3-tk-luc). It has no inhibitory activity against RIE cells that do not express PPARγ. |
| ln Vivo |
Inolitazone (RS5444) coupled with paclitaxel demonstrated enhanced antiproliferative effect in cell culture and decreased ATC tumor development. When inolitazone was provided via the food to athymic nude mice prior to DRO tumor cell implantation, tumor growth was suppressed in a dose-response manner. At the highest dose, 0.025% Inolitazone decreased growth by 94.4% on day 32 compared to the control. In this therapy group, 5 of 10 mice did not develop overt tumors. On day 32, in the 0.0025% treatment group, tumor growth was decreased by 62.3% compared to the control, whereas the 0.00025% dose showed no growth inhibitory efficacy compared to the control. Tumors were allowed to build nests in mice, and mice were treated with 0.025% Inolitazone commencing 1 week following DRO or ARO tumor cell implantation. On day 35, Inolitazone-treated rats revealed 68.9% tumor growth inhibition in DRO tumors and 48.3% tumor growth inhibition in ARO tumors compared to their respective controls [1].
Inolitazone inhibits tumor growth in a dose-responsive manner in nude mice implanted with DRO tumor cells. At a dose of 0.025%, Inolitazone inhibited tumor growth by 94.4% on day 32. At 0.0025%, tumor growth was inhibited by 62.3%. It also showed growth inhibition rates of 68.9% for DRO tumors and 48.3% for ARO tumors at day 35. Inolitazone plus Paclitaxel showed additive antiproliferative activity in cell culture. |
| Enzyme Assay |
The primary in vitro assay for Inolitazone is a PPARγ activation assay using a luciferase reporter gene fused to a PPRE response element (PPRE3-tk-luc). Cells are transfected with PPARγ and the reporter construct, and then treated with the compound. The activation of PPARγ is measured by the increase in luciferase activity. Growth inhibition assays are performed using various cancer cell lines.
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| Cell Assay |
Cellular assays for Inolitazone involve treating cancer cells, such as DRO cells, with the compound and measuring cell proliferation, cell cycle distribution, and the expression of target genes like p21WAF1/CIP1. The compound's ability to activate PPARγ is confirmed by measuring the expression of PPARγ target genes.
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| Animal Protocol |
In vivo animal experiments have been conducted using nude mice implanted with DRO or ARO tumor cells. Inolitazone was administered orally, and tumor growth was monitored. The compound's ability to inhibit tumor growth was assessed by measuring tumor volume and weight. Its effects on body weight and toxicity were also evaluated.
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| ADME/Pharmacokinetics |
Inolitazone has a molecular weight of 502.58 g/mol and a molecular formula of C27H26N4O4S. It is a small molecule that is typically used as a research reagent. Its density is 1.39 g/cm3. It is stored as a powder at -20°C for up to 3 years or in solvent at -80°C for up to 1 year.
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| Toxicity/Toxicokinetics |
The toxicological profile of Inolitazone is not extensively detailed in the provided sources. As a research compound, it is not intended for human use. Standard safety precautions should be followed when handling. Its safety would need to be established through preclinical studies if it were to be developed for therapeutic applications.
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| References |
[1]. Copland JA, et al. Novel high-affinity PPARgamma agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1. Oncogene. 2006 Apr 13;25(16):2304-17.
[2]. Marlow LA, et al. Reactivation of suppressed RhoB is a critical step for the inhibition of anaplastic thyroid cancer growth. Cancer Res. 2009 Feb 15;69(4):1536-44 |
| Additional Infomation |
Efatutazone has been used in clinical trials to treat various tumors, including lymphoma, liposarcoma, solid tumors, multiple myeloma, and recurrent thyroid cancer. Efatutazone is a highly bioavailable thiazolidinedione drug and an agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), possessing potential antitumor activity. Efatutazone binds to and activates PPAR-γ, thereby inducing cell differentiation and apoptosis, ultimately leading to reduced cell proliferation. PPAR-γ is a nuclear hormone receptor and ligand-activated transcription factor that regulates gene expression involved in macromolecular metabolism and cell differentiation (especially adipocyte differentiation).
Inolitazone (RS5444, Efatutazone) is a novel, high-affinity PPARγ agonist with an IC50 of approximately 0.8 nM for growth inhibition. It specifically activates PPARγ without affecting PPARα or PPARδ. Inolitazone has shown potent antitumor activity in preclinical models, including anaplastic thyroid cancer. It is available from various chemical suppliers for research purposes. |
| Molecular Formula |
C27H26N4O4S
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| Molecular Weight |
502.58
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| Exact Mass |
502.167
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| CAS # |
223132-37-4
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| Related CAS # |
Inolitazone dihydrochloride;223132-38-5
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| PubChem CID |
9832447
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
794.6±60.0 °C at 760 mmHg
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| Flash Point |
434.4±32.9 °C
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| Vapour Pressure |
0.0±2.8 mmHg at 25°C
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| Index of Refraction |
1.706
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| LogP |
3.61
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
782
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(N1)SC(CC2=CC=C(OCC3=NC4=CC=C(OC5=CC(C)=C(N)C(C)=C5)C=C4N3C)C=C2)C1=O
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| InChi Key |
JCYNMRJCUYVDBC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H26N4O4S/c1-15-10-20(11-16(2)25(15)28)35-19-8-9-21-22(13-19)31(3)24(29-21)14-34-18-6-4-17(5-7-18)12-23-26(32)30-27(33)36-23/h4-11,13,23H,12,14,28H2,1-3H3,(H,30,32,33)
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| Chemical Name |
5-[[4-[[6-(4-amino-3,5-dimethylphenoxy)-1-methylbenzimidazol-2-yl]methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
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| Synonyms |
RS5444 CS 7017 CS-7017, CS7017
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9897 mL | 9.9487 mL | 19.8973 mL | |
| 5 mM | 0.3979 mL | 1.9897 mL | 3.9795 mL | |
| 10 mM | 0.1990 mL | 0.9949 mL | 1.9897 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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