TG100-115

SKU: orb1224271

Description

A potent, selective PI3Kγ/δ with IC50 of 83/235 nM, respectively; shows no significant inhibitory activity against pI3Kα and β, and a broad panel of kinases (IC50>1 uM); potently inhibits edema and inflammation in response to multiple mediators known to participate in myocardial infarction, such as VEGF and platelet-activating factor, without effect on endothelial cell mitogenesis; provides potent cardioprotection, reduces infarct development and preserves myocardial function in animal MI models.COPD Discontinued(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.\n(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.

Key Properties

• CAS Number: 677297-51-7
• MW: 346.3428
• Purity: >98% (HPLC)
• Formula: C₁₈H₁₄N₆O₂
• SMILES: OC1=CC=CC(C2=NC3=NC(N)=NC(N)=C3N=C2C4=CC=CC(O)=C4)=C1
• Target: PI3K
• Solubility: 10 mM in DMSO

Bioactivity

• 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.
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• 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.
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Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

TG100115 | TG100 115

Quick Database Links

Gene Symbol

PI3K