生物活性

• 描述Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3'-position hydroxyl groups of phosphatidylinositol (PtdIns) to generate 3-phosphoinositides (PtdIns(3)P), which are essential in the activation of downstream signaling responses including cell growth, proliferation and metabolism. Vacuolar protein sorting 34 (Vps34) is the isoform of class III PI3K that are critical in controlling vesicular protein sorting. Vps34-IN-1 is a highly selective inhibitor of Vps34 with an IC50 of 25nM in vitro without affecting the activity of class I and class II PI3Ks isoforms. Vps34-IN-1 suppressed the level of PtdIns(3)P on endosome membranes in a dose-dependent manner with 80% loss at 1.0 μM and 50% loss at 0.1 μM. The significant effect of Vps34-IN-1 in reducing PtdIns(3)P at endosome was found within 1 min, and the maximal effect was within 2min. U2OS cells treated with 1μM Vps34-IN-1 within 1 min lost 50-60% phosphorylation of serum- and glucocorticoid-regulated protein kinase-3 (SGK3), a protein kinase interacted with PtdIns(3)P. The combination of 1μM Vps34-IN-1 and 0.5μM GDC-0941, a class I PI3K inhibitor, decreased the activity and phosphorylation of SGK3 by 80-90% in U2OS cells. Treatment with 1μM Vps34-IN-1 reduced the activation of SGK2 ~4-fold in HEK293 cells that were stimulated with insulin-like growth factor between 2 min to 8 hours. When healthy human donors was treated with 1μM VPS34-IN-1 for 1 hour, the thrombus growth was reduced by nearly 40%.
• 作用机制Vps34-IN-1inhibits Vps34 signaling pathway via rapid perturbation of PtdIns(3)P synthesis at endosomal membrane.

• 动物研究
  剂量	Mice: 20 mg/kg[5] (p.o.)
  给药途径	p.o.