产品说明书

	同义名 :	TAK-475
	CAS号 :	189060-13-7
	货号 :	A357554
	分子式 :	C33H41ClN2O9
	纯度 :	98%
	分子量 :	645.14
	MDL号 :	MFCD06407873
	存储条件：	粉末 Sealed in dry,Store in freezer, under -20°C 液体 -20°C:3-6个月-80°C:12个月
	溶解度 :	-
	动物实验配方：

生物活性

描述

Squalene synthase (SQS) catalyzes the conversion of two farnesyl pyrophosphates to squalene, an important intermediate in between isoprene and valuable triterpenoids[3]. Squalene synthase was up-regulated in CL1-5 cells and in the tumor regions of the lung cancer specimens. Loss of function or knockdown of SQS significantly inhibited invasion/migration and metastasis in cell and animal models and vice versa. High expression of SQS was significantly associated with poor prognosis among patients with lung cancer. Mechanistically, SQS contributed to a lipid-raft-localized enrichment of tumor necrosis factor receptor 1 in a cholesterol-dependent manner, which resulted in the enhancement of nuclear factor-κB activation leading to matrix metallopeptidase 1 up-regulation[4]. Lapaquistat acetate (TAK-475) is a squalene synthase inhibitor, blocking the conversion of farnesyl diphosphate (FPP) to squalene in the cholesterol biosynthesis pathway[5]. Lapaquistat acetate is effective at lowering low-density lipoprotein cholesterol, but it might cause liver damage. Lapaquistat acetate is used for hypercholesterolemia and mevalonate kinase deficiency (MKD) research[6]. Lapaquistat acetate (diet supplemented; 100 or 200 mg/kg; 32 weeks) decreases plasma cholesterol and triglyceride levels. It delays progression of coronary atherosclerosis and changes coronary atheromatous plaques from unstable, macrophage/lipid accumulation-rich, lesions to stable fibromuscular lesions in vivo[7].

临床研究
NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT00143676	Hypercholesterolemia	Phase 3	Completed	-	-
NCT00286481	Hypercholesterolemia	Phase 3	Completed	-	-
NCT00256178	Hypercholesterolemia	Phase 3	Completed	-	-

实验方案
	1mg	5mg	10mg
1 mM 5 mM 10 mM	1.55mL 0.31mL 0.16mL	7.75mL 1.55mL 0.78mL	15.50mL 3.10mL 1.55mL

参考文献

[1]Stein EA, Bays H, et al. Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011 May 10;123(18):1974-85. [2]Shiomi M, Yamada S, et al. Lapaquistat acetate, a squalene synthase inhibitor, changes macrophage/lipid-rich coronary plaques of hypercholesterolaemic rabbits into fibrous lesions. Br J Pharmacol. 2008 Jul;154(5):949-57. [3]Yafeng Song,et al. Production of Squalene in Bacillus subtilis by Squalene Synthase Screening and Metabolic Engineering. J Agric Food Chem. 2020 Apr 15;68(15):4447-4455. [4]Yi-Fang Yang,et al. Squalene synthase induces tumor necrosis factor receptor 1 enrichment in lipid rafts to promote lung cancer metastasis. Am J Respir Crit Care Med.2014 Sep 15;190(6):675-87. [5]Stein EA, et al. Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia. Circulation. 2011 May 10;123(18):1974-85. [6]Marcuzzi A, et al. Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice. Curr Med Chem. 2018;25(24):2783-2796. [7]M Shiomi, et al. Lapaquistat acetate, a squalene synthase inhibitor, changes macrophage/lipid-rich coronary plaques of hypercholesterolaemic rabbits into fibrous lesions. Br J Pharmacol. 2008 Jul;154(5):949-57.