Inolitazone

Inolitazone 是一种新型的高亲和力 PPARγ 激动剂，其生物活性依赖于 PPARγ，抑制生长的 IC50 为 0.8 nM。

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库存: 现货

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5mg

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货号: ajci10650
CAS: 223132-37-4
别名: 5-[[4-[[6-(4-氨基-3,5-二甲基苯氧基)-1-甲基-1H-苯并咪唑-2-基]甲氧基]苯基]甲基]-2,4-噻唑啉二酮,Efatutazone; CS-7017; RS5444
分子式: C27H26N4O4S
分子量: 502.58
纯度: >98%
溶解度: Soluble in DMSO
储存: Store at -20°C
库存: 现货

Background

Description: IC50 Value: 0.8 nM [1] Inolitazone(RS5444) is a novel high-affinity PPARgamma agonist, which activates PPARgamma with an EC50 about 1/50th that of rosiglitazone and has no effect on RIE cells that do not express PPARgamma. in vitro: In vitro, the IC50 for growth inhibition is approximately 0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited three- to fourfold in nude mice. siRNA against PPARgamma and a pharmacological antagonist demonstrated that functional PPARgamma was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21WAF1/CIP1 [1]. RS5444inhibited culture growth and caused irreversible G1 arrest, but did not induce apoptosis. In addition, RS5444 caused dramatic changes in cellular morphology which were associated with increased motility and diminished cellular adherence, but no increase in the ability of such cells to digest and invade Matrigel [2]. Treatment with RS5444 leads to the up-regulation of RhoB and subsequent activation of p21, and that silencing of RhoB by RNAi blocks the ability of RS5444 to induce p21 and to inhibit ATC cells proliferation [3]. in vivo: The median peak efatutazone blood level was 8.6 ng/mL for 0.15-mg dosing vs 22.0 ng/mL for 0.3-mg twice daily dosing [4]. Although efatutazone treatment did not reduce percentage of mice developing invasive cancer, it significantly reduced prevalence of noninvasive cancer and total number of cancers per mouse and increased prevalence of well-differentiated cancer subtypes not usually seen in this mouse model [5]. Clinical trial: CS-7017 in Combination with Carboplatin/Paclitaxel in Subjects with Stage IIIb/IV Non-small Cell Lung Cancer (NSCLC). Phase 1b

Protocol

Cell experiment:

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].

Animal experiment:

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.

参考文献:

[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.