TG100-115 is a PI3Kγ/δ inhibitor (IC50: 83/235 nM), with fewer effects on PI3Kα/β.

PI3Kγ:83 nM

在患心肌梗塞的啮齿目动物和猪模型中,TG100-115（0.5-5 mg/kg）具有有效的心脏保护功能,阻止梗塞恶化,保存心机功能.在Miles实验模型中,TG100-115（1-5 mg/kg）使大鼠的水肿和炎症降低.TG100-115（5 mg/kg）可使小鼠体内Sema3A或血管内皮生长因子相关的血管通透性显著降低,表明这两种因子对血管通透性的诱导作用可能依赖于PI3Kγ/δ.在患哮喘鼠模型,TG100-115可使肺嗜酸性粒细胞增多症显著减弱,并使白细胞介素13和粘蛋白积累受到抑制.

在人脐静脉内皮细胞中,TG100-115（10 μM）不影响细胞增殖和VEGF刺激的ERK磷酸化,但会阻断其他血管内皮生长因子信号通路, 如VE-钙粘蛋白磷酸化,从而抑制血管内皮生长因子诱导的VE钙粘蛋白整体水平提高。 TG100-115（0.125-10 μM）对FGF刺激的Akt磷酸化也有抑制作用。TG100-115对PI3Kα/β的抑制效果很弱（IC50：1.2/1.3 mM）。TG100-115对血管内皮生长因子调节的p70S6和mTOR激酶磷酸化有抑制作用。

PI3K assays: Forty mL of reaction buffer (20 mM Tris/4 mM MgCl2/10 mM NaCl, pH 7.4) containing 50 mM D-myo-phosphatidylinositol 4,5-bisphosphate substrate and the desired PI3K isoform are aliquoted to 96-well plates; kinase concentrations are 250-500 ng/well, such that linear kinetics are achieved over 90 min. TG100-115 is then added as 2.5 mL of a DMSO stock to final concentration range of 100 mM to 1 nM. Reactions are initiated by addition of 10 mL of ATP to a final concentration of 3 mM, and after 90 min, 50 mL of Kinase-Glo reagent added to quantify residual ATP levels; luminosity is measured using an Ultra 384 instrument. Control reactions omitting either TG100-115 or substrate are also performed. IC50 values are derived from experimental data by nonlinear curve fitting using Prism Version 4.

Cells plated in 96-well cluster plates (5 × 103 cells/well) are cultured in assay medium (containing 0.5% serum and 50 ng/ml VEGF) in the presence or absence of TG100-115, and cell numbers are quantified by XTT assay 24, 48, or 72 hours late(Only for Reference)