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 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|
|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.
|Solubility||DMSO: ≥ 30 mg/mL|
Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo.
Honda A, et al. ACS Med Chem Lett. 2015 Nov 13;7(1):72-6. PMID: 26819669.
Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.
Dowdle WE, et al. Nat Cell Biol. 2014 Nov;16(11):1069-79. PMID: 25327288.
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