TG100-115

TG100-115 is a selective PI3Kγ/PI3Kδ inhibitor with IC₅₀s of 83 and 235 nM, respectively. IC50 & Target: IC50: 83 nM (PI3Kγ), 235 nM (PI3Kδ)^[1] In Vitro: TG100-115 inhibits PI3Kγ and PI3Kδ with IC₅₀s of 83 and 235 nM, respectively, whereas both PI3Kα and PI3Kβ are relatively unaffected (IC₅₀ values >1 μM). As a gauge of general specificity, TG100-115 is also assayed against a 133 protein kinase panel, none of which are inhibited at IC₅₀ values <1 μM. TG100-115 potently inhibits edema and inflammation in response to multiple mediators known to participate in myocardial infarction, including vascular endothelial growth factor and platelet-activating factor; by contrast, endothelial cell mitogenesis, a repair process important to tissue survival after ischemic damage^[1]. In Vivo: To correlate these in vivo responses with the molecular target of interest, PI3K pathway signaling is monitored through western blot analyses of Akt phosphorylation (a PI3K-mediated event). VEGF injection i.v. in mice induces a rapid Akt phosphorylation readily detectable in lung lysates, pretreatment with TG100-115 blocks this response. Blockade is seen with TG100-115 doses as low as 0.5 mg/kg and persists over a period of several hours. In initial dose-ranging studies, generally equivalent responses are observed using TG100-115 doses of 0.5-10 mg/kg, and we therefore elected to conduct a statistically powered test at the lowest dose. Animals dosed with TG100-115 as a single 0.5 mg/kg i.v. bolus 30 min after reperfusion developed smaller infarcts vs. vehicle-treated controls. Measuring infarct area as percent of total LV ischemic area, infarct size is reduced by 35% (P=0.04). Viable tissue within the ischemic zone is increased by 37% (P=0.04), directly demonstrating the cardioprotective effect of PI3Kγ/δ inhibition^[1].