SAR245409 (XL765)

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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SAR245409 (XL765) Chemical Structure

SAR245409 (XL765) Chemical Structure
Molecular Weight: 599.66

Validation & Quality Control

Customer Reviews(3)

Quality Control & MSDS

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SAR245409 (XL765) is available in the following compound libraries:

Product Information

  • Inhibition Profile
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  • Research Area

Product Description

Biological Activity

Description 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 mTOR p110α p110β p110γ p110δ
IC50 157 nM 39 nM 113 nM 9 nM 43 nM [1]
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
Dosages 30 mg/kg
Administration Oral gavage once a day
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00485719 Completed Cancer Sanofi 2007-06 Phase 1
NCT00704080 Completed Mixed Gliomas|Malignant Gliomas|Glioblastoma Multiforme Sanofi 2008-08 Phase 1
NCT00777699 Completed Cancer|Non-Small Cell Lung Cancer Sanofi 2008-08 Phase 1
NCT01082068 Completed Breast Cancer Sanofi 2010-06 Phase 1|Phase 2
NCT01240460 Completed Glioblastoma|Astrocytoma, Grade IV Sanofi 2011-01 Phase 1

Chemical Information

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

C31H29N5O6S

CAS No. 1349796-36-6
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Syonnyms N/A
Solubility (25°C) * In vitro DMSO 12 mg/mL (20 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-

Preparing Stock Solutions

Stock Solution (1ml DMSO) 1mM 10mM 20mM 30mM
Mass(mg) 0.59966 5.9966 11.9932 -

Research Area

Customer Reviews (3)


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Rating
Source Endocrinology, 2013, 154(3), 1247-59. 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.

Click to enlarge
Rating
Source Endocrinology, 2013, 154(3), 1247-59. 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. 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 Citations (1)

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