1. Cell Cycle/DNA Damage
    NF-κB
  2. PPAR

Inolitazone dihydrochloride (Synonyms: Efatutazone; CS-7017; RS5444)

Cat. No.: HY-14792B Purity: 97.34%
Data Sheet SDS Handling Instructions

Inolitazone dihydrochloride is a novel high-affinity PPARγ agonist that is dependent upon PPARγ for its biological activity with IC50 of 0.8 nM for growth inhibition.

For research use only. We do not sell to patients.
Inolitazone dihydrochloride Chemical Structure

Inolitazone dihydrochloride Chemical Structure

CAS No. : 223132-38-5

Size Price Stock Quantity
10 mM * 1 mL in DMSO $453 In-stock
5 mg $358 In-stock
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Other Forms of Inolitazone dihydrochloride:

  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

Inolitazone dihydrochloride is a novel high-affinity PPARγ agonist that is dependent upon PPARγ for its biological activity with IC50 of 0.8 nM for growth inhibition.

IC50 & Target

PPARγ[1]

In Vitro

Inolitazone (RS5444) dihydrochloride upregulates the cell cycle kinase inhibitor, p21WAF1/CIP1. Silencing p21WAF1/CIP1 rendered cells insensitive to Inolitazone. A 10 nM dose of Inolitazone activates PPARγ:RXRα-dependent transcription as demonstrated in a transient transfection assay utilizing a PPRE response element fused to a luciferase reporter gene (PPRE3-tk-luc). DRO cells are treated in culture with Inolitazone, Rosiglitazone, or Troglitazone at the indicated concentrations. DRO cells are transiently transfected with PPRE3-tk-luc to examine effective concentrations at which EC50 occurs. The EC50s are 1 nM (Inolitazone), 65 nM (Rosiglitazone) and 631 nM (Troglitazone). Similarly, the calculated inhibitory concentration at IC50 is 0.8 nM for Inolitazone, 75 nM for Rosiglitazone, and 1412 nM for Troglitazone. Inolitazone specifically activates PPARγ, but not PPARα or PPARδ. Exposure of 10 nM Inolitazone following transient transfection with the appropriate PPAR isoform (γ, α, or δ) and PPAR response element linked to a luciferase reporter in RIE rat small intestinal cell line, which does not express PPARs, yields increased luciferase activity only in the presence of PPARγ and PPRE3-tk-luc[1]. DRO cells are growth inhibited by 10 nM Inolitazone (RS5444) through a PPARγ-dependent mechanism[2].

In Vivo

Inolitazone (RS5444) plus Paclitaxel demonstrate additive antiproliferative activity in cell culture and minimal ATC tumor growth. When Inolitazone is administered in the diet to athymic nude mice prior to DRO tumor cell implantation, tumor growth is inhibited in a dose responsive fashion. At the highest dose, 0.025% Inolitazone inhibits growth on day 32 by 94.4% as compared to that of control. In this treatment group, five of 10 animals do not develop demonstrable tumors. In the 0.0025% treatment group, tumor growth is inhibited by 62.3% compared to that of control on day 32 while the 0.00025% dose demonstrated no growth inhibitory activity as compared to control. Tumors is nest allowed to establish in the mouse and began 0.025% Inolitazone treatment of mice 1 week after DRO or ARO tumor cell implantation. Inolitazone treated animals demonstrate tumor growth inhibition of 68.9% in DRO tumors and 48.3% in ARO tumors as compared to that of their respective controls on day 35[1].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT00986440 Daiichi Sankyo Inc. Colorectal Cancer July 2009 Phase 2
NCT01199068 Daiichi Sankyo Co., Ltd.|ICON Clinical Research|Daiichi Sankyo Inc. Carcinoma, Non-Small-Cell Lung June 2010 Phase 1
NCT00881569 Daiichi Sankyo Inc. Cancer March 2009 Phase 1
NCT01504490 Georgetown University|Daiichi Sankyo Inc. Solid Tumors|Lymphoma|Multiple Myeloma December 2011 Phase 1
NCT01199055 Daiichi Sankyo Co., Ltd.|ICON Clinical Research|Daiichi Sankyo Inc. Carcinoma, Non-Small-Cell Lung March 2010 Phase 1
NCT01101334 Daiichi Sankyo Inc. Advanced Non-small Cell Lung Cancer March 2010 Phase 2
NCT00408434 Daiichi Sankyo Inc. Neoplasm November 2006 Phase 1
NCT02249949 Alliance for Clinical Trials in Oncology|National Cancer Institute (NCI)|Daiichi Sankyo Inc. Liposarcoma October 2014 Phase 2
NCT02152137 Alliance for Clinical Trials in Oncology|National Cancer Institute (NCI)|Daiichi Sankyo Inc. Anaplastic Thyroid Cancer|Recurrent Thyroid Cancer September 2014 Phase 2
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 1.7376 mL 8.6879 mL 17.3759 mL
5 mM 0.3475 mL 1.7376 mL 3.4752 mL
10 mM 0.1738 mL 0.8688 mL 1.7376 mL
Cell Assay
[1]

Inolitazone (RS5444) is prepared in DMSO and stored, and then diluted with appropriate medium before use[1].

DRO90-1 (DRO) and ARO81 (ARO) cells are plated in 12-well culture plates in triplicate for each condition at an initial concentration of 2×104 cells/well. After overnight incubation, cells are treated with either Inolitazone, Rosiglitazone, Troglitazone, GW9662, or Paclitaxel diluted in DMSO at concentrations indicated in figure legends. All cells receive identical volumes of DMSO and are exposed to each drug for 6 days with medium and drug changed every 48 h. After 6 days, cells are washed with PBS, trypsinized and counted by Beckman Coulter Counter[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Mice[1]
Suspensions of 1×106/0.1 mL DRO or ARO cells in RPMI medium are injected subcutaneously in one flank of 3-4 week athymic female nude mice. Mice are changed to specialized diets either 1 week prior or 1 week after tumor implantation and randomly assigned to experimental or control groups with 10 mice per group. Diets consisted either placebo, 0.00025%, 0.0025%, or 0.025% Inolitazone formulated into the diet. Mice weighed between 20-25 g and consume on average 4 g of food per day. For combinatorial studies either placebo, 10 mg/kg or 15 mg/kg paclitaxel is injected i.p. twice weekly. Tumors are measured every 3-4 days for 35 days with calipers and tumor volumes are calculated by the formula: 0.5236(a×b×c), where a is the shortest diameter, b is the diameter perpendicular to a and c is the diameter height. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

575.51

Formula

C₂₇H₂₈Cl₂N₄O₄S

CAS No.

223132-38-5

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 245 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

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Product Name:
Inolitazone dihydrochloride
Cat. No.:
HY-14792B
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