Voxtalisib (SAR245409, XL765)

Voxtalisib (SAR245409, XL765) is a dual inhibitor of mTOR/PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. Phase 1/2.

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Voxtalisib (SAR245409, XL765) Chemical Structure

Voxtalisib (SAR245409, XL765) Chemical Structure
Molecular Weight: 599.66

Validation & Quality Control

Customer Product Validation(3)

Quality Control & MSDS

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Product Description

Biological Activity

Description Voxtalisib (SAR245409, XL765) is a dual inhibitor of mTOR/PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. Phase 1/2.
Targets PI3Kγ [1] PI3Kα [1] PI3Kδ [1] PI3Kβ [1]

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IC50 9 nM 39 nM 43 nM 113 nM
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. [1] 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. [2]
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. [2] 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. [3]
Features

Protocol(Only for Reference)

Cell Assay: [2]

Cell lines Pancreatic cancer cell lines (HcG25, Panc89, PA-TU8988T, Panc2.13, MiaPaCa2, Panc10.05, Panc8.13, BxPC-3, etc.)
Concentrations Dissolved in DMSO, final concentration ~10 μM
Incubation Time 24, 48, 72 hours
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.

Animal Study: [2]

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 gavage once a day

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

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.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-06-27)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01936363 Active, not recruiting Ovarian Cancer EMD Serono|Sanofi September 2013 Phase 2
NCT01587040 Recruiting Neoplasm Malignant Sanofi July 2012 Phase 1|Phase 2
NCT01596270 Completed Neoplasm Malignant Sanofi June 2012 Phase 1
NCT01410513 Completed Indolent Non-Hodgkin Lymphoma|Mantle Cell Lymphoma|Chronic Lymphocytic Leukemia Sanofi December 2011 Phase 1
NCT01403636 Completed Lymphoma Sanofi October 2011 Phase 2

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Chemical Information

Download Voxtalisib (SAR245409, XL765) SDF
Molecular Weight (MW) 599.66
Formula

C31H29N5O6S

CAS No. 1349796-36-6
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 12 mg/mL (20.01 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name Benzamide, N-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-

Customer Product Validation (3)


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Rating
Source Endocrinology 2013 154, 1247-59. Voxtalisib (SAR245409, XL765) purchased from Selleck
Method Serum GH and PRL secretion assay
Cell Lines female nude mice
Concentrations 25 mg/kg
Incubation Time
Results The TMZ/XL765 combination decreased both serum rat-GH and rat-PRL dramatically compared with either agent alone.

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Rating
Source Endocrinology 2013 154, 1247-59. Voxtalisib (SAR245409, XL765) purchased from Selleck
Method TUNEL staining
Cell Lines GH3 cells
Concentrations 25 mg/kg
Incubation Time
Results TMZ (5 mg/kg) or XL765 (25 mg/kg) alone moderately decreased the number of Ki-67-positive cells (Figure A and B) and increased the number of TUNEL-positive cells (Figure C and D) compared with the DMSO-treated tumors. However, the TMZ/XL765 combination dramatically increased the number of TUNEL-positive cells and decreased the number of Ki-67-positivecells compared with either agent alone.

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Rating
Source Dr. Zhang of Tianjin Medical University. Voxtalisib (SAR245409, XL765) purchased from Selleck
Method Western blot
Cell Lines A549 cells
Concentrations 0-1 μM
Incubation Time 3 h
Results XL765 treatment resulted in a reduction of Akt phosphorylation in A549 cells.

Product Use Citation (4)

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