"目录号: HY-14792
Cell Cycle/DNA DamageNF-κB-
Inolitazone(RS5444; CS-7017)是新型PPARγ高亲和性激动剂，EC50为rosiglitazone的五十分之一，对于不表达PPARγ的RIE细胞无抑制性。
PPAR
相关产品
GW9662-Rosiglitazone-Retinoic acid-Troglitazone-Pioglitazone hydrochloride-Elafibranor-GW 501516-CDDO-Im-Fenofibrate-T0070907-Wy-14643-GW0742-Daidzein-FH535-BMS-687453-
生物活性
Description
Inolitazone a novel high-affinityPPARγagonist that is dependent upon PPARγ for its biological activity withIC50of 0.8 nM for growth inhibition.
IC50& Target
PPARγ[1]
In Vitro
Inolitazone (RS5444) upregulates the cell cycle kinase inhibitor, p21WAF1/CIP1. Silencing p21WAF1/CIP1rendered 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 EC50occurs. The EC50s are 1 nM (Inolitazone), 65 nM (Rosiglitazone) and 631 nM (Troglitazone). Similarly, the calculated inhibitory concentration at IC50is 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
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
[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.