| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
Vps34 (IC50 = 1.2 nM); Vps34 (Kd = 1.5 nM); Autophagy
SAR-405 targets PIK3C3/Vps34 (vacuolar protein sorting 34), a class III phosphatidylinositol 3-kinase that plays a critical role in autophagy and endosomal trafficking. It is a highly selective inhibitor with an IC50 of 1.2 nM. By inhibiting Vps34, SAR-405 blocks the production of phosphatidylinositol 3-phosphate (PI3P), which is essential for autophagosome formation and autophagy initiation. |
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| ln Vitro |
SAR405 is an inhibitor that was highly specific for Vps34 with regard to protein kinases and other phosphoinositide kinases. The human recombinant Vps34 enzyme phosphorylates a PtdIns substrate with an IC50 of 1 nM for SAR405 in this process. This compound 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, corresponding to a residence half-life, t1/2, of 3.8 min. SAR405 has no effect on the phosphorylation of Akt. SAR405 affects the movement of vesicles from late endosomes to lysosomes. Additionally, it is a strong inhibitor of autophagy[1].
In vitro, SAR-405 inhibits Vps34 with an IC50 of 1.2 nM and a Kd of 1.5 nM. It prevents autophagosome formation with an IC50 of 42 nM. The compound inhibits starvation- or mTOR inhibition-induced autophagy and synergizes with MTOR inhibition in tumor cells, leading to enhanced anticancer activity. SAR-405 has been shown to inhibit autophagy while preventing MTOR activity in tumor cells. |
| ln Vivo |
SAR405 is a first-in-class, selective, and ATP-competitive PI3K class III (PIK3C3) isoform Vps34 inhibitor.
In vivo, SAR-405 has been evaluated in preclinical models of cancer, neurodegenerative diseases, and metabolic disorders. As a Vps34 inhibitor, it modulates autophagy-related processes in vivo. The compound's specificity for Vps34 allows for precise modulation of autophagy in preclinical studies, making it a valuable tool for investigating the role of autophagy in various disease contexts. |
| Enzyme Assay |
KiNativ profiling is performed. Jurkat cell lysates are treated with 1 μM of SAR405. After 15-min incubation, the desthiobiotin-ATP-acylphosphate probe is added and incubated for 10 min. Samples are prepared for targeted MS analysis. In a nutshell, samples are denatured and then reduced in alkylate to prepare them for trypsin digestion. Trypsin is then used to digest the samples, and desthiobiotinylated peptides are then enriched on streptavidin resin. Using a unique data collection technique, enriched probe-labeled peptides are analyzed by LC tandem MS on an ion trap mass spectrometer from Thermo-LTQ. Extraction of distinctive fragment ion signals from targeted MS/MS spectra and comparison of signals in control and treated samples are used for all quantification.
In vitro enzyme assays for Vps34 inhibition involve incubating recombinant Vps34 enzyme with phosphatidylinositol and ATP in the presence of varying concentrations of SAR-405. The production of phosphatidylinositol 3-phosphate (PI3P) is measured using radioactive or HTRF-based assays. IC50 values are calculated from dose-response curves to determine the compound's potency. |
| Cell Assay |
GFP-LC3 HeLa cells are starved for 2 h in EBSS plus 10 μM hydroxychloroquine with Vps34 compound or DMSO. GFP-LC3 H1299 cells are treated with 1 μM AZD8055 for 4 hours while being fed (DMEM, 10% FCS, 1 mM L-glutamine with SAR405, or DMSO) to test the mTOR inhibitor. The nuclei of the cells are then stained with 2 g/ml Hoechst 33342 after they have been fixed with 4% PFA. An imaging cytometer is used to analyze fluorescence. When there are more than four green spots per cell, with a total of 25 fields acquired, cells are deemed positive. The product's activity is estimated.
Cellular assays are performed using various cancer cell lines. Cells are treated with SAR-405 at concentrations ranging from 0.1 nM to 10 μM. Autophagy is assessed by measuring LC3-II accumulation or p62 degradation via Western blot. Autophagosome formation is evaluated using fluorescence microscopy with GFP-LC3 reporter cells. Cell viability is measured by MTT or CellTiter-Glo assays to assess anticancer activity. |
| Animal Protocol |
Nude mice
2 mg/kg Oral gavage In vivo studies are conducted in tumor-bearing mouse models or models of neurodegenerative diseases. SAR-405 is administered intraperitoneally or orally at various doses. Tumor volume is measured periodically, and autophagy markers (LC3-II, p62) in tumor tissues are assessed by Western blot or immunohistochemistry. Combination studies with MTOR inhibitors may be performed to evaluate synergistic antitumor effects. |
| ADME/Pharmacokinetics |
SAR-405 (molecular weight 493.56, formula C₂₅H₂₇N₇O₃S) is a small-molecule compound. It is soluble in DMSO and is typically stored at -20°C (powder form, 3 years) or -20°C (solution, 6 months). Its physicochemical properties support its use in both in vitro and in vivo studies.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies of SAR-405 have been limited, as the compound is primarily used as a research tool. As a Vps34 inhibitor, its toxicity profile is related to inhibition of autophagy and endosomal trafficking. No significant toxicity has been reported at the concentrations used for in vitro and in vivo studies.
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| References | |
| Additional Infomation |
A Vps34 inhibitor with antitumor activity; structure described in the first article.
SAR-405 is a potent and selective Vps34 inhibitor widely used in cancer, neurodegenerative disease, and metabolic disorder research to better understand the implications of autophagy inhibition. Its mechanism involves inhibiting PIK3C3/Vps34, thereby blocking PI3P production and autophagosome formation. The compound's specificity for Vps34 allows for precise modulation of autophagy-related processes in preclinical studies, making it a valuable tool for investigating the role of autophagy in various disease contexts. |
| Molecular Formula |
C19H21CLF3N5O2
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|---|---|
| Molecular Weight |
443.8506
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| Exact Mass |
443.133
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| Elemental Analysis |
C, 51.42; H, 4.77; Cl, 7.99; F, 12.84; N, 15.78; O, 7.21
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| CAS # |
1523406-39-4
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| Related CAS # |
SAR405 R enantiomer;1946010-79-2
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| PubChem CID |
72709209
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
526.5±60.0 °C at 760 mmHg
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| Flash Point |
272.2±32.9 °C
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| Vapour Pressure |
0.0±1.4 mmHg at 25°C
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| Index of Refraction |
1.635
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| LogP |
1.97
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
30
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| Complexity |
731
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| Defined Atom Stereocenter Count |
2
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| SMILES |
ClC1=C([H])N=C([H])C(=C1[H])C([H])([H])N1C2=NC(=C([H])C(N2C([H])([H])C([H])([H])[C@@]1([H])C(F)(F)F)=O)N1C([H])([H])C([H])([H])OC([H])([H])[C@@]1([H])C([H])([H])[H]
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| InChi Key |
SPDQRCUBFSRAFI-DOMZBBRYSA-N
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| InChi Code |
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
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| 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
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| Synonyms |
SAR405; SAR 405; SAR-405
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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: 27~89 mg/mL (60.8~200.5 mM)
H2O: <0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.63 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 (5.63 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 (5.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (5.63 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. Solubility in Formulation 5: 2% DMSO+30% PEG 300+2% Tween 80+ddH2O: 4mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2530 mL | 11.2651 mL | 22.5301 mL | |
| 5 mM | 0.4506 mL | 2.2530 mL | 4.5060 mL | |
| 10 mM | 0.2253 mL | 1.1265 mL | 2.2530 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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