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Voxtalisib (XL765) Analogue

Voxtalisib (XL765) Analogue

Item no.	S1523-50
Manufacturer	Selleckchem
CASRN	1349796-36-6
Amount	50 mg
Quantity options	10 mg 1 g 10 g 10 mM/1 ml 200 mg 5 mg 50 mg 5 g
Category	Oncology Inhibitors & Compound Libraries Small Molecules By Organ Testicular & Prostate Cancer Pancreatic Cancer
Type	Inhibitors
Specific against	other
Smiles	CC1=C(C=C(C=C1)C(=O)NC2=CC=C(C=C2)S(=O)(=O)NC3=NC4=CC=CC=C4N=C3NC5=CC(=CC(=C5)OC)OC)OC
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	SAR245409
Similar products	XL765
Available
Manufacturer - Targets	PI3K, MTOR
Storage Conditions	2 years -80 in solvent
Molecular Weight	599, 66
Administration	Oral gavage once a day
Animal Models	Female Nu/Nu mice inoculated s.c. with BxPC-3 cells
Cell lines	Pancreatic cancer cell lines (HcG25, Panc89, PA-TU8988T, Panc2.13, MiaPaCa2, Panc10.05, Panc8.13, BxPC-3, etc.)
Clinical Trials	A Phase I study to evaluate the safety and tolerability of XL765 in combination with erlotinib in subjects with solid tumors has been completed.
Concentrations	Dissolved in DMSO, final concentration ca.10 uM
Dosages	30 mg/kg
Formulation	Solubilized in water/10 mM HCl
IC50	157 nM, 157 nM, 157 nM, 157 nM, 157 nM, 157 nM
In vitro	XL765 is active against class I PI3K (IC50 = 39, 113, 9 and 43 nM for p110alpha, beta, gamma and delta, respectively). XL765 also inhibits DNA-PK (IC50 = 150 nM) and mTOR (IC50 = 157 nM) but not XL-147 which shows IC50 values of > 15 uM. [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]
Incubation Time	24, 48, 72 hours
Kinase Assay	[1]
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.
Solubility (25C)	DMSO 15 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Information	Voxtalisib (SAR245409, XL765) Analogue is a dual inhibitor of mTOR/PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. Phase 1/2.
Chemical Name	Benzamide, N-[4-[[[3-[(3, 5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-

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