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SAR405

现货
Catalog No.
A8883
ATP竞争性的Vps34抑制剂。
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,270.00
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2mg
¥ 990.00
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5mg
¥ 1,300.00
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10mg
¥ 2,400.00
现货
25mg
¥ 4,650.00
现货

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Background

SAR405 is a selective ATP-competitive inhibitor of Vps34 with a Kd value of 1.5 nM.
Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that plays important role in autophagy. Vps34 was originally described in yeast to be involved in vesicle trafficking. SAR405 is a first-in-class catalytic Vps34 inhibitor and represents a unique pharmacological tool to investigate the biology around this protein. This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. This is the first potent and specific Vps34 inhibitor described so far. Inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy.
Using SAR405, inhibition of Vps34 did not affect early events of endocytosis but resulted in an accumulation of swollen late endosome-lysosomes. A defect of cathepsin D maturation was also identified upon treatment with SAR405, indicating that the function of lysosomes is impaired. This result is in agreement with a previous report using Vps34 siRNA, which affects vesicle trafficking from late endosomes to lysosomes.
SAR405 had an IC50 of 1 nM in the phosphorylation of a PtdIns substrate by human recombinant Vps34 enzyme. This relocalization of the GFP-FYVE indicated that SAR405 inhibits PtdIns3P formation. As SAR405 was found to not be active up to 10 μM on class I and class II PI3Ks as well as on mTOR. Binding of SAR405 to the ATP site of protein and lipid kinases from the lysate of Jurkat cells was measured after incubation at 1μM, which is more than 600-fold the KD for recombinant Vps34. SAR405 did not affect the Akt phosphorylation in the PC3 cell line at concentrations up to 10 μM.
References:
[1]. Ronan B, Flamand O1, Vescovi L et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol. 2014 Dec;10(12):1013-9.

文献引用

Chemical Properties

StorageStore at -20°C
M.Wt443.85
Cas No.1523406-39-4
FormulaC19H21ClF3N5O2
Solubility≥22.2mg/mL in DMSO
Chemical Name(S)-1-((5-chloropyridin-3-yl)methyl)-8-((R)-3-methylmorpholino)-2-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one
SDFDownload SDF
Canonical SMILESC[C@H]1N(C(N=C2N3CC[C@@H](C(F)(F)F)N2CC4=CN=CC(Cl)=C4)=CC3=O)CCOC1
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验[1]:

Vps34 细胞实验

在专用的Vps34细胞实验中评价SAR405的活性。使用GFP-FYVE转染的HeLa细胞系,SAR405的治疗引起GFP-FYVE在细胞内的再定位而不影响GFP强度。1 μM温育后测量SAR405与来自Jurkat细胞裂解物的蛋白质和脂质激酶的ATP位点的结合,其KD为重组Vps34的600倍以上。结果证实SAR405与内源性Vps34有效的结合,产生大于 94%的抑制。

细胞实验: [1]

细胞系

GFP-LCLC3 HeLa 细胞,GFP-LCLC3 H1299细胞

制备方法

该化合物在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

16 h-24 h

实验结果

在RKO细胞中,SAR405处理24小时导致p62蛋白的剂量依赖性积累,SAR405处理16小时成熟组织蛋白酶D显著减少。SAR405也完全抑制GFP-LCLC3 HeLa细胞中自噬体的形成。此外,在GFP-LCLC3 H1299细胞中,SAR405阻止由mTOR抑制剂诱导的自噬,并与Everolimus 具有协同性。

References:

1. Ronan B, Flamand O1, Vescovi L et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol. 2014 Dec;10(12):1013-9.

质量控制

化学结构

SAR405

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