product name Voxtalisib (XL765) Analogue
Description: Voxtalisib (also called SAR245409, XL765) Analogue is a dual inhibitor of mTOR/PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. In PA cell lines, combination of XL765 and TMZ blocked the cell growth and led to apoptosis. In a variety of tumor cell lines that mutated on PI3K signaling, XL765 inhibited PIP3 formation in the membrane and AKT/p70S6K/S6 phosphorylation. In GH3 xenograft tumor mouse models, combination use of XL765 and TMZ inhibited tumor growth, reduced serum GH and prolactin levels with no increased systemic side effects.
References: Mol Cancer Ther. 2012 Aug;11(8):1758-69.
599.66
Formula
C31H29N5O6S
CAS No.
1349796-36-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 12 mg/mL (20.0 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
30% PEG400+0.5% Tween80+5% Propylene glycol: 30 mg/mL
Chemical Name
N-[4-[[3-(3,5-dimethoxyanilino)quinoxalin-2-yl]sulfamoyl]phenyl]-3-methoxy-4-methylbenzamide
other peoduct :
| In Vitro | Kinase Assay:
Cell Assay: Cells (Pancreatic cancer cell lines (HcG25, Panc89, PA-TU8988T, Panc2.13, MiaPaCa2, Panc10.05, Panc8.13, BxPC-3, etc.) 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. 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. |
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| 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. |
| Animal model | Female Nu/Nu mice inoculated s.c. with BxPC-3 cells |
| Formulation & Dosage | Dissolved in water/10 mM HCl; 30mg/kg; oral |
| References | [1] Garcia-Echeverria C, et al. Oncogene, 2008, 27(41), 5511-5526.; [2] Mirzoeva OK, et al. J Mol Med, 2011, 89(9), 877-889. |
