TG100-115 is a potent small molecule PI3K γ/δ inhibitor potently inhibited edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor. TG100-115, inhibited PI3Kγ and -δ (IC50 values of 83 and 235 nM, respectively), whereas both PI3Kα and -β were relatively unaffected (IC50 values >1 μM). TG100-115 also blocked histamine-induced permeability, as predicted based on PI3K's role in GPCR signaling. Additionally, TG100-115 did not block VEGF-induced angiogenesis in vivo.
|Cell lines||Human umbilical vein EC|
|Preparation method||Cell proliferation assay.
Human umbilical vein EC plated in 96-well cluster plates (5,000 cells/well) were cultured in assay medium (containing 0.5% serum and 50 ng/ml VEGF) in the presence or absence of test compounds (10 μM), and cell numbers were quantified by XTT assay (Promega, Madison, WI) 24, 48, or 72 h later.
|Incubation time||24, 48, or 72 h|
|Animal models||Rodent and porcine MI models|
|Formulation||either PEG or sulfobutyl ether β-cyclodextrin (CyDex, Lenexa, KS) formulations|
|Dosages||0.5mg/kg or 1mg/kg|
|Administration||i.v. at 0–3 h after reperfusion|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Cancer Discov (2016). Figure 4.TG100-115|
|Cell Lines||WT mice|
|Incubation Time||48 hours|
|Results||Intravital imaging revealed that control-treated mice exhibited large pancreatic tumors and multiple metastases, whereas TG100-115–treated mice had signifi cantly smaller pancreatic tumors and few, if any, metastases|
Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury.
Doukas J, et al. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19866-71. PMID: 17172449.
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