生物活性

• 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].

• 动物研究
  剂量	Mice: 20 mg/kg[1] (p.o.)
  给药途径	p.o.