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SAR245409

Cat. No. M1849
SAR245409 Structure
Synonym:

Voxtalisib, XL765

Size Price Availability Quantity
Free Sample (0.5-1 mg)  USD 0 In stock
10mg USD 180 In stock
50mg USD 600 In stock
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Quality Control
Biological Activity

In vitro: XL765 is active against class I PI3K (IC50 = 39, 113, 9 and 43 nM for p110α, β, γ and δ, respectively). XL765 also inhibits DNA-PK (IC50 = 150 nM) and mTOR (IC50 = 157 nM) but not XL-147 which shows IC50 values of > 15 μM. XL765 treatment results in decreased cell viability in 13 PDA cell lines in a dose-dependent manner. XL765, a dual-target PI3K/mTOR inhibitor, inhibits cell growth and apoptosis in many more cell lines and at lower concentrations as compared to the PI3K-selective inhibitors XL147 and PIK90. The effect can be recapitulated by using combinations of single-targeted compounds. XL765 significantly reduces phosphorylation of the mTOR targets S6, S6K, and 4EBP1, which is associated with greater apoptosis induction rather than to PI3K inhibition alone. XL765 treatment causes accumulation of autophagosomes in MIAPaCa-2 cells, and results in significant dose-dependent AVO induction and LC3-II stimulation in MIAPaCa-2 cells stably expressing a LC3-GFP construct. 

In vivo: The combination of XL765 (30 mg/kg) with chloroquine (50 mg/kg) results in significant inhibition of BxPC-3 xenograft growth in mice models, while XL765 alone at the same dose has no inhibitory effect. Oral administration of XL765 results in greater than 12-fold reduction in median tumor bioluminescence compared to control and improvement in median survival in nude mice implanted intracranially with GBM 39-luc cells. XL765 in combination with temozolomide (TMZ) yields a 140-fold reduction in median bioluminescence with a trend toward improvement in median survival compared with TMZ alone.

Customer Product Validations & Biological Datas
Source Mol Cancer Ther (2014). Figure 2.XL765
Method Western immunoblotting
Cell Lines MCF7 cells
Concentrations 10 μmol/L
Incubation Time 20 h
Results XL765 was identified following optimization of a pyridopyrimidinone scaffold for in vivo PI3K/mTOR pathway inhibition and drug-like properties.
Protocol
Cell Experiment
Cell lines Pancreatic cancer cell lines
Preparation method Cells are treated with XL765 24 hours after plating and harvested for apoptosis or autophagy assays at 24, 48, or 72 hours after XL765 treatment. Apoptosis is determined by total percentage of annexin V-positive cells by fluorescence-activated cell sorting (FACS). Acidic vesicular organelles (AVOs) are detected in XL765-treated cells by vital staining with acridine orange. The degree of AVO formation is expressed as fold increase of acridine orange fluorescence intensity (FL3) in XL765-treated cells versus control cells.
Concentrations ~10 μM
Incubation time 24, 48, 72 h
Animal Experiment
Animal models Female Nu/Nu mice inoculated s.c. with BxPC-3 cells
Formulation Solubilized in water/10 mM HCl
Dosages 30 mg/kg
Administration oral
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
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.

Chemical Information
Molecular Weight 270.29
Formula C13H14N6O
CAS Number 934493-76-2
Purity 100.00%
Solubility 54 mg/mL in DMSO
Storage at -20°C
References

Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice.
Dai C, et al. Endocrinology. 2013 Mar;154(3):1247-59. PMID: 23384836.

Targeting the PI3K/mTOR Axis, Alone and in Combination with Autophagy Blockade, for the Treatment of Malignant Peripheral Nerve Sheath Tumors.
Ghadimi et al. Mol Cancer Ther. 2012 Aug;11(8):1758-69. PMID: 22848094.

Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma.
Mirzoeva et al. J Mol Med (Berl). 2011 Sep;89(9):877-89. PMID: 21678117.

Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide.
Prasad et al. Neuro Oncol. 2011 Apr;13(4):384-92. PMID: 21317208.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: SAR245409, Voxtalisib, XL765 supplier, PI3K, inhibitors

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