SAR405

Selective ATP-competitive inhibitor of Vps34 CAS# 1523406-39-4

SAR405

Catalog No. BCC4006----Order now to get a substantial discount!

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Quality Control of SAR405

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Chemical structure

SAR405

3D structure

Chemical Properties of SAR405

Cas No. 1523406-39-4 SDF Download SDF
PubChem ID 72709209 Appearance Powder
Formula C19H21ClF3N5O2 M.Wt 443.85
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 27 mg/mL (60.83 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name (8S)-9-[(5-chloropyridin-3-yl)methyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(trifluoromethyl)-7,8-dihydro-6H-pyrimido[1,2-a]pyrimidin-4-one
SMILES CC1COCCN1C2=CC(=O)N3CCC(N(C3=N2)CC4=CC(=CN=C4)Cl)C(F)(F)F
Standard InChIKey SPDQRCUBFSRAFI-DOMZBBRYSA-N
Standard InChI InChI=1S/C19H21ClF3N5O2/c1-12-11-30-5-4-26(12)16-7-17(29)27-3-2-15(19(21,22)23)28(18(27)25-16)10-13-6-14(20)9-24-8-13/h6-9,12,15H,2-5,10-11H2,1H3/t12-,15+/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of SAR405

DescriptionSAR405 is a PIK3C3/Vps34 inhibitor with an IC50 of 1.2 nM. SAR405 also is a proximal inhibitor of the autophagy machinery.In Vitro:SAR405 is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM). SAR405 has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. Inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. SAR405 shows a binding equilibrium constant KD of 1.52±0.77 nM (±s.d.) and a dissociation rate constant, koff, of 3.03 ± 0.55 10-3 s-1, corresponding to a residence half-life, t1/2, of 3.8 min. The activity of SAR405 is next evaluated on a dedicated Vps34 cellular assay using a GFP-FYVE–transfected HeLa cell line[1]. SAR405 is a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. SAR405 is a proximal inhibitor of the autophagy machinery. SAR405 prevents autophagosome formation with an IC50 of 42 nM. Treatment of starved cells with SAR405 completely inhibits the conversion to LC3-II in a dose-dependent manner. The effect of SAR405 on autophagy is then investigated. The GFP-LC3 model is used for the HTS and confirmed its activity on starved cells (IC50=419 nM). The conversion of LC3-I into LC3-II is also analyzed by western blotting on wild-type HeLa and H1299 cells[2].

References:
[1]. Ronan B, et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol. 2014 Dec;10(12):1013-9. [2]. Pasquier B. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. Autophagy. 2015 Apr 3;11(4):725-6.

Protocol

Kinase experiment [1]:

Vps34 cellular assay

The activity of SAR405 was evaluated on a dedicated Vps34 cellular assay. Using a GFP-FYVE–transfected HeLa cell line, treatment with SAR405 triggered the relocalization of GFP-FYVE inside the cell without affecting GFP intensity. Binding of SAR405 to the ATP site of protein and lipid kinases from the lysate of Jurkat cells was measured after incubation at 1 μM, which is more than 600-fold the KD for recombinant Vps34. Results confirmed very potent binding to endogenous Vps34 (>94% inhibition)。

Cell experiment [1]:

Cell lines

GFP-LCLC3 HeLa cells ; GFP-LCLC3 H1299 cells

Preparation method

Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

16 h-24 h

Applications

In RKO cells, 24-h SAR405 treatment leads to a dose-dependent accumulation of p62 protein and 16-h of SAR405 treatment shows a significant decrease of mature cathepsin D. SAR405 also completely inhibits the formation of autophagosomes in GFP-LCLC3 HeLa cells. In addition, SAR405 prevents autophagy induced by mTOR inhibitor and synergizes with everolimus in GFP-LCLC3 H1299 cells,

References:

1. Ronan B, Flamand O1, Vescovi L et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol. 2014 Dec;10(12):1013-9.

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Preparing Stock Solutions of SAR405

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.253 mL 11.2651 mL 22.5301 mL 45.0603 mL 56.3253 mL
5 mM 0.4506 mL 2.253 mL 4.506 mL 9.0121 mL 11.2651 mL
10 mM 0.2253 mL 1.1265 mL 2.253 mL 4.506 mL 5.6325 mL
50 mM 0.0451 mL 0.2253 mL 0.4506 mL 0.9012 mL 1.1265 mL
100 mM 0.0225 mL 0.1127 mL 0.2253 mL 0.4506 mL 0.5633 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on SAR405

SAR405 is a selective ATP-competitive inhibitor of Vps34 with a Kd value of 1.5 nM.
Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that plays important role in autophagy. Vps34 was originally described in yeast to be involved in vesicle trafficking. SAR405 is a first-in-class catalytic Vps34 inhibitor and represents a unique pharmacological tool to investigate the biology around this protein. This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. This is the first potent and specific Vps34 inhibitor described so far. Inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy.
Using SAR405, inhibition of Vps34 did not affect early events of endocytosis but resulted in an accumulation of swollen late endosome-lysosomes. A defect of cathepsin D maturation was also identified upon treatment with SAR405, indicating that the function of lysosomes is impaired. This result is in agreement with a previous report using Vps34 siRNA, which affects vesicle trafficking from late endosomes to lysosomes.
SAR405 had an IC50 of 1 nM in the phosphorylation of a PtdIns substrate by human recombinant Vps34 enzyme. This relocalization of the GFP-FYVE indicated that SAR405 inhibits PtdIns3P formation. As SAR405 was found to not be active up to 10 μM on class I and class II PI3Ks as well as on mTOR. Binding of SAR405 to the ATP site of protein and lipid kinases from the lysate of Jurkat cells was measured after incubation at 1μM, which is more than 600-fold the KD for recombinant Vps34. SAR405 did not affect the Akt phosphorylation in the PC3 cell line at concentrations up to 10 μM.
References:
[1]. Ronan B, Flamand O1, Vescovi L et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol. 2014 Dec;10(12):1013-9.

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References on SAR405

SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells.[Pubmed:25905679]

Autophagy. 2015 Apr 3;11(4):725-6.

Autophagy plays an important role in cancer and it has been suggested that it functions not only as a tumor suppressor pathway to prevent tumor initiation, but also as a prosurvival pathway that helps tumor cells endure metabolic stress and resist death triggered by chemotherapeutic agents. We recently described the discovery of inhibitors of PIK3C3/Vps34 (phosphatidylinositol 3-kinase, catalytic subunit type 3), the lipid kinase component of the class III phosphatidylinositol 3-kinase (PtdIns3K). This PtdIns3K isoform has attracted significant attention in recent years because of its role in autophagy. Following chemical optimization we identified SAR405, a low molecular mass kinase inhibitor of PIK3C3, highly potent and selective with regard to other lipid and protein kinases. We demonstrated that inhibiting the catalytic activity of PIK3C3 disrupts vesicle trafficking from late endosomes to lysosomes. SAR405 treatment also inhibits autophagy induced either by starvation or by MTOR (mechanistic target of rapamycin) inhibition. Finally our results show that combining SAR405 with everolimus, the FDA-approved MTOR inhibitor, results in a significant synergy on the reduction of cell proliferation using renal tumor cells. This result indicates a potential therapeutic application for PIK3C3 inhibitors in cancer.

Description

SAR405 is a first-in-class, selective, and ATP-competitive PI3K class III (PIK3C3) isoform Vps34 inhibitor (IC50=1.2 nM; Kd=1.5 nM). SAR405 inhibits autophagy induced either by starvation or by mTOR inhibition. Anticancer activity.

Keywords:

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