TG100-115

PI3K

346, 34

Rat (Sprague-Dawley) myocardial ischemia (MI) model

TG100-115 is currently under a Phase I/II clinical trial in myocardial infarction.

0.5–5 mg/kg

83 nM, 83 nM, 83 nM, 83 nM, 83 nM, 83 nM

In Miles assay models, TG100-115 (1–5 mg/kg) reduces edema formation and inflammation in rats. In rigorous rodent and porcine models of myocardial ischemia (MI), TG100-115 (0.5–5 mg/kg) provides potent cardioprotection, limits infarct development, and preserves myocardial function. [1] In mice, TG100-115 (5 mg/kg) markedly diminishes vascular permeability (VP) in response to either Sema3A or VEGF, indicating that both factors may depend on PI3Kgamma/delta to induce VP. [3] In a mouse asthma model, aerosolized TG100-115 markedly reduces the pulmonary eosinophilia, inhibits interleukin-13 and mucin accumulation. [4]

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.

DMSO 9 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL

6, 7-Bis(3-hydroxyphenyl)pteridine-2, 4-diamine