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Vps34-IN-4

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Chemical Structure| 1383716-46-8 同义名 : VPS34 inhibitor 1;Compound 19;PIK-III analogue
CAS号 : 1383716-46-8
货号 : A332678
分子式 : C21H25N7O
纯度 : 98%+
分子量 : 391.469
MDL号 : MFCD31718218
存储条件：

粉末 Keep in dark place,Sealed in dry,2-8°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
靶点

  • Vps34

    VPS34, IC50:15 nM
描述 VPS34 is the primordial member of the PI3 kinase family and the only known class III PI3 kinase that can phosphorylate the D-3 position on the inositol ring of phosphatidylinositol (PtdIns) to produce PtdIns3P. VPS34 inhibitor 1, also called Spautin-1, promotes the degradation of Vps34PI3 kinase complexes by inhibiting two ubiquitin specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes[1]. Compound 19, PIK-III analogue is a potent and selective inhibitor of VPS34 with an IC50 value of 15 nM. Compound 19 is extraordinarily selective over other lipid and protein kinases. The ability of compound 19 to prevent the degradation of autophagy substrates p62, NCOA4, NBR1, NDP52, and FTH1 is similar to PIK-III. In addition, treatment of cells with compound 19 leads to an increase in the lipidated and nonlipidated forms of LC3 similar to previous reports using PIK-III. The pharmacokinetic profile of analogue 19 is determined in C57BL/6 mice. After oral administration at 10 mg/kg, the compound is rapidly absorbed and showed moderate mean systemic clearance (30 mL/min/kg, approximately 33% of hepatic blood flow), with good oral bioavailability (F% = 47). Based on these PK parameters and the cellular activity, compound 19 constitutes a suitable candidate for in vivo studies. Upon oral administration of compound 19 at 50 mg/kg twice a day (BID) for 7 days, LC3-II accumulates consistent with reduced autophagic capacity in time-dependent manner[2]. When treated D17, MDCK, OVC-cMES-103, OVC-cOSA-31,OVC-cOSA-75 and OVC-cOSA-106 with spautin-1 either with low dose(5μM) and high dose(100μM) alone or combination with doxorubicin, cell killing was enhanced and colony formation was inhibited by the combination methods in low dose[3].
作用机制 VPS34 inhibitor 1 inhibits deubiquitination activity of USP10 and USP13 and promote degradation of Beclin1 in Vps34 complexes[1].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.55mL

0.51mL

0.26mL

12.77mL

2.55mL

1.28mL

25.54mL

5.11mL

2.55mL
参考文献

[1] Liu J. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell. 2011 Sep 30;147(1):223-34. doi: 10.1016/j.cell.2011.08.037.

[2]Honda A. Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo. ACS Med Chem Lett. 2015 Nov 13;7(1):72-6. doi: 10.1021/acsmedchemlett.5b00335.

[3]Schott CR. The autophagy inhibitor spautin-1, either alone or combined with doxorubicin, decreases cell survival and colony formation in canine appendicular osteosarcoma cells. PLoS One. 2018 Oct 29;13(10):e0206427. doi: 10.1371/journal.pone.0206427.