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| 25mg |
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Purity: ≥98%
VPS34-IN2 (PIK-III; Vps34-PIK-III) is a novel, potent and selective inhibitor of VPS34 (IC50 = 18 nM) with the ability to modulate autophagy in Vivo. PIK-III blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. In contrast to related kinases like PI(3)K, PIK-III binds to a particular hydrophobic pocket. The acute inhibition of autophagy and de novo lipidation of LC3 by PIK-III results in the stabilization of autophagy substrates.
| Targets |
Vps34 (IC50 = 18 nM); PI(3)Kδ (IC50 = 1.2 μM); PI(3)Kγ (IC50 = 3.04 μM); PI(3)Kα (IC50 = 3.96 μM)
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| ln Vitro |
VPS34 enzymatic function is essential for LC3 lipidation in mammalian cells and PIK-III is a robust inhibitor of autophagy and LC3 lipidation in mammalian cells. In H4 cells, both in basal conditions and when autophagy is induced using the mTOR inhibitor AZD8055, PIK-III reduces the formation of autolysosomes and boosts the cytosolic signal of LC3. PIK-III prevents the removal of mitochondria in a mitophagy model induced by CCCP. In H4 and PSN1 cells, treatment with PIK-III causes LC3-I levels to rise. In Panc10.05 cells, PIK-III raises the levels of LC3-II concurrently with LC3-I, indicating a cell type-specific response[1].
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| ln Vivo |
The single-dose, fast-absorbing Vps34-PIK-III (10 mg/kg; valve) has a strong valve biological utilization (F% = 47) and a modest mean systemic clearance (30 mL/min/kg, or around 33% of hepatic blood flow) [1].
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| Cell Assay |
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 listed substances, fixed, stained with Hoechst 33342, and imaged by automated acquisition. HeLa cells expressing GFP-Parkin are treated with PIK-III for 12 hours, then added CCCP for another 12 hours. The cells are then fixed, stained for endogenous Tom20, and imaged.
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| Animal Protocol |
Animal/Disease Models: C57BL/6 mice[1].
Doses: 10 mg/kg; 2 mg/kg Route of Administration: oral; intravenous (iv) (iv)injection; individual Experimental Results: 1.19 pharmacokinetic/PK/PK parameters of Vps34-PIK-III in C57BL/6 mice [1]. IV (2 mg/kg) PO (10 mg/kg) Tmax (h) 0.7 Cmax (nM) 2994 AUCinf (nM·h) 2855 6725 t1/2 (h) 1.2 CL (mL/min/kg) 30 Vdss ( Liter/kg)1.5F(%)47% |
| References |
[1]. Honda A, et al. Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy in Vivo. ACS Med Chem Lett. 2015 Nov 13;7(1):72-6.
[2]. Liu F, et al. PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor. Cell Death Dis. 2020 Jun 8;11(6):427. [3]. Dowdle WE, et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol. 2014 Nov;16(11):1069-79. |
| Molecular Formula |
C17H17N7
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|---|---|
| Molecular Weight |
319.3638
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| Exact Mass |
319.1545
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| Elemental Analysis |
C, 63.93; H, 5.37; N, 30.70
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| CAS # |
1383716-40-2
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| Related CAS # |
1383716-40-2
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| Appearance |
Solid powder
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| SMILES |
C1CC1CC2=NC(=NC=C2C3=NC(=NC=C3)NC4=CC=NC=C4)N
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| InChi Key |
XXSDLQLNIVFIJI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H17N7/c18-16-21-10-13(15(23-16)9-11-1-2-11)14-5-8-20-17(24-14)22-12-3-6-19-7-4-12/h3-8,10-11H,1-2,9H2,(H2,18,21,23)(H,19,20,22,24)
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| Chemical Name |
4-(cyclopropylmethyl)-5-[2-(pyridin-4-ylamino)pyrimidin-4-yl]pyrimidin-2-amine
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| Synonyms |
Vps34 PIK-III; Vps34-PIK III; VPS34-IN2; VPS34-IN 2; Vps34-PIK-III; PIK-III; PIK III; PIKIII; VPS34-IN-2
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 31~63 mg/mL (97~197.3 mM)
Ethanol: ~63 mg/mL (~197.3 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1313 mL | 15.6563 mL | 31.3126 mL | |
| 5 mM | 0.6263 mL | 3.1313 mL | 6.2625 mL | |
| 10 mM | 0.3131 mL | 1.5656 mL | 3.1313 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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