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Voxtalisib (XL765)

Name: Voxtalisib (XL765)
Brand: Selleck Chemicals
SKU: S7646
Rating: 5 (13 reviews)

Catalog No.S7646 Synonyms: SAR245409

For research use only.

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.

CAS No. 934493-76-2

Selleck's Voxtalisib (XL765) has been cited by 13 publications

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PI3K Signaling Pathway Map

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] (Cell-free assay)	PI3Kα ^[1] (Cell-free assay)	PI3Kδ ^[1] (Cell-free assay)	PI3Kβ ^[1] (Cell-free assay)	DNA-PK ^[1] (Cell-free assay)	Click to View More Targets
9 nM	39 nM	43 nM	113 nM	150 nM	Click to View More Targets

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]

Protocol (from reference)

Cell Research:

^[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 Research:

^[2]

Animal Models: Female Nu/Nu mice inoculated s.c. with BxPC-3 cells
Dosages: 30 mg/kg
Administration: Oral gavage once a day

References

Solubility (25°C)

In vitro	DMSO	54 mg/mL (199.78 mM)
	Water	Insoluble
	Ethanol	Insoluble

Chemical Information

Molecular Weight	270.29
Formula	C₁₃H₁₄N₆O
CAS No.	934493-76-2
Storage	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
Smiles	CCN1C2=NC(=NC(=C2C=C(C1=O)C3=CC=NN3)C)N

Download Voxtalisib (XL765) SDF

In vivo Formulation Calculator (Clear solution)

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Clinical Trial Information

NCT Number	Recruitment	Interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT01596270	Completed	Drug: SAR245409	Neoplasm Malignant	Sanofi	June 2012	Phase 1
NCT01410513	Completed	Drug: SAR245409	Indolent Non-Hodgkin Lymphoma\|Mantle Cell Lymphoma\|Chronic Lymphocytic Leukemia	Sanofi	December 2011	Phase 1
NCT01240460	Completed	Drug: XL765 (SAR245409)\|Drug: XL147 (SAR245408)	Glioblastoma\|Astrocytoma Grade IV	Sanofi	January 2011	Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

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