Search Site
Related Products
SAR405Selective ATP-competitive inhibitor of Vps34

SAR405

Catalog No. A8883
Size Price Stock Qty
10mM (in 1mL DMSO) $1,120.00 In stock
1mg $280.00 In stock
5mg $700.00 In stock

Tel: +1-832-696-8203

Email: sales@apexbt.com

Worldwide Distributors

Sample solution is provided at 25 µL, 10mM.

Quality Control

Chemical structure

SAR405

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.

SAR405 Dilution Calculator

Concentration (start)
x
Volume (start)
=
Concentration (final)
x
Volume (final)
 
 
 
C1
V1
C2
V2

calculate

SAR405 Molarity Calculator

Mass
=
Concentration
x
Volume
x
MW*
 
 
 
g/mol

calculate

Chemical Properties

Cas No. 1523406-39-4 SDF Download SDF
Chemical Name (S)-1-((5-chloropyridin-3-yl)methyl)-8-((R)-3-methylmorpholino)-2-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one
Canonical SMILES C[C@H]1N(C(N=C2N3CC[C@@H](C(F)(F)F)N2CC4=CN=CC(Cl)=C4)=CC3=O)CCOC1
Formula C19H21ClF3N5O2 M.Wt 443.85
Solubility Soluble in DMSO Storage Store at -20°C
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.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Background

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.