PIK-III is a VPS34 inhibitor which blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis. It has IC50 values of 18 nM and 1.2 μM for VPS34 and PI(3)Kδ, respectively. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. In H4 cells, PIK-III inhibits the formation of autolysosomes and increases the cytosolic signal of LC3 under basal conditions and when autophagy is induced with the mTOR inhibitor AZD8055. Treatment with Vps34-PIK-III leads to an increase in the levels of LC3-I in H4 and PSN1 cells.
Cell Experiment | |
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Cell lines | H4 cells/ HeLa cells |
Preparation method | To determine whether inhibition of VPS34 function impacts autophagy, LC3 and known autophagy substrates such as damaged mitochondria or the autophagy cargo receptor p62 are monitored. H4 cells expressing mCherry-GFP-LC3 are treated overnight with the indicated compounds, fixed, stained with Hoechst 33342 and imaged by automated acquisition. HeLa cells expressing GFP-Parkin are treated with PIK-III for 12 h followed by the addition of CCCP for 12 h, fixed, stained for endogenous Tom20 and imaged. |
Concentrations | 2.5μM in H4 cells/5μM in Hela cells |
Incubation time | overnight for H4 cells/12h for Hela cells |
Animal Experiment | |
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Animal models | |
Formulation | |
Dosages | |
Administration |
Molecular Weight | 319.36 |
Formula | C17H17N7 |
CAS Number | 1383716-40-2 |
Solubility (25°C) | DMSO: ≥ 30 mg/mL |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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