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Purity: ≥98%
Voxtalisib (also known as SAR245409, XL765) is a potent, orally bioavailable small molecule and dual inhibitor of mTOR/PI3K (mammalian target of rapamycin/phosphatidylinositol 3 kinase) with anticancer activity. With an IC50 of 9 nM, it primarily inhibits p110 while also inhibiting DNA-PK and mTOR. Combining Voxtalisib and TMZ (temozolomide) inhibited cell growth and caused apoptosis in PA cell lines. PIP3 formation in the membrane and AKT/p70S6K/S6 phosphorylation were inhibited by XL765 in a number of tumor cell lines with PI3K signaling mutations. Combining Voxtalisib and TMZ prevented tumor growth and decreased serum GH and prolactin levels in mouse models of GH3 xenograft tumors without increasing systemic side effects.
| Targets |
p110γ (IC50 = 9 nM); p110α (IC50 = 39 nM); p110δ (IC50 = 43 nM); p110β (IC50 = 113 nM); mTOR (IC50 = 157 nM); mTORC1 (IC50 = 160 nM); mTORC2 (IC50 = 910 nM); DNA-PK (IC50 = 150 nM)
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| ln Vitro |
XL765 is effective against class I PI3K (IC50 = 39, 113, 9 and 43 nM for p110α, β, γ and δ, respectively). XL765 also inhibits DNA-PK and mTOR, but not XL-147, which exhibits IC50 values greater than > 15 μM. [1] In 13 PDA cell lines, treatment with XL765 reduces cell viability in a dose-dependent manner. Comparatively to the PI3K-selective inhibitors XL147 and PIK90, XL765, a dual-target PI3K/mTOR inhibitor, inhibits cell growth and apoptosis in many more cell lines and at lower concentrations. Combinations of single-targeted compounds can be used to replicate the effect. Compared to PI3K inhibition alone, XL765 significantly lowers the phosphorylation of the mTOR targets S6, S6K, and 4EBP1, which increases the induction of apoptosis. 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. In MIAPaCa-2 cells that are stably expressing an LC3-GFP construct, XL765 treatment results in significant dose-dependent AVO induction and LC3-II stimulation. It also causes autophagosome accumulation in MIAPaCa-2 cells. [2]
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| ln Vivo |
In mice models, BxPC-3 xenograft growth is significantly inhibited by the combination of XL765 (30 mg/kg) and chloroquine (50 mg/kg), whereas XL765 alone at the same dose has no inhibitory effect. [2] In nude mice implanted intracranially with GBM 39-luc cells, oral administration of XL765 results in a greater than 12-fold reduction in median tumor bioluminescence compared to control and an improvement in median survival. In comparison to temozolomide (TMZ) alone, the combination of XL765 and TMZ results in a 140-fold reduction in median bioluminescence and a slight improvement in median survival. [3]
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| Enzyme Assay |
The Cell Proliferation ELISA, Bromodeoxyuridine Chemiluminescence Kit is used to measure cell proliferation. The ATP Bioluminescence Assay is used to determine cytotoxicity as follows: PC-3, MCF7, A549, LS174T, MDA-MB-468, U87-MG, and OVCAR are examples of the following: Three cells are plated onto 96-well microtiter plates in culture medium at densities of 7×103, 1.5×104, 6×103, 7×103, 7×103, 6×103, 1.5×104 cells per well, respectively. After 18 hours of incubation at 37 °C and 5% CO2, the cells are then treated with serial dilutions of the compound in medium with a final concentration of 0.3% DMSO. For each compound concentration, three duplicate wells are utilized. Media containing 0.3% DMSO is used in control wells. Cell viability is then determined using the ViaLight HS Kit after cultures have been incubated at 37°C and 5% CO2 for an additional 24 hours[2].
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| Cell Assay |
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. Fluorescence-activated cell sorting (FACS) measures the overall percentage of annexin V-positive cells to determine the level of apoptosis. Acridine orange vital staining is used to identify acidic vesicular organelles (AVOs) in cells that have been exposed to XL765. The amount of AVO formation is measured by the ratio of the increase in acridine orange fluorescence intensity (FL3) in XL765-treated cells to control cells.
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| Animal Protocol |
Mice: Mice that are athymic and nude are used for in vivo efficacy tests. At 37°C in a humidified 5% CO2 environment, tumor cells are cultured in DMEM enriched with 10% FBS (20% for PC-3 and OVCAR-3 cells), Penicillin-Streptomycin, and non-essential amino acids. In 0.1 mL of ice-cold water, 1 to 5×106 cells are harvested by brief trypsinization on day 0. Hanks Female athymic nude mice have Balanced Salt Solutions implanted subcutaneously (OVCAR-3) or intradermally (MCF7 and U-87 MG) into the hind flank. When tumor cells are implanted in the MCF7 model, an estrogen pellet (IRA) is inserted subcutaneously at the nape of the neck. Male nude mice between the ages of 5 and 8 weeks old have their hind-flanks subcutaneously implanted with a total of 3×106 PC-3 cells. Up until staging and dose initiation, tumor growth is measured every week with calipers. Body and tumor weights are measured throughout the dosing period. Voxtalisib (XL-765) is formulated in sterile water/10 mM HCl or water and given orally via gavage at the prescribed doses and schedules with a dose volume of 10 mL/kg.
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| References | |
| Additional Infomation |
2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-7-pyrido[2,3-d]pyrimidinone is a pyrazolopyridine.
Voxtalisib has been used in trials studying the treatment of Cancer, Melanoma, Lymphoma, Glioblastoma, and Breast Cancer, among others. Voxtalisib is an orally bioavailable small molecule targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) kinases in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Voxtalisib inhibits both PI3K kinase and mTOR kinase, which may result in tumor cell apoptosis and growth inhibition in susceptible tumor cell populations. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated in a PI3K-independent fashion in response to nutrient and energy deprivation. Accordingly, this agent maybe more potent compared to an agent that inhibits either PI3K kinase or mTOR kinase alone. |
| Molecular Formula |
C13H14N6O
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|---|---|
| Molecular Weight |
270.29
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| Exact Mass |
270.122
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| Elemental Analysis |
C, 57.77; H, 5.22; N, 31.09; O, 5.92
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| CAS # |
934493-76-2
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| Related CAS # |
1349796-36-6;934493-76-2;
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| PubChem CID |
16123056
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| Appearance |
White solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.674
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| LogP |
5.95
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
20
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| Complexity |
425
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1N(CC)C2N=C(N)N=C(C=2C=C1C1C=CNN=1)C
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| InChi Key |
RGHYDLZMTYDBDT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C13H14N6O/c1-3-19-11-8(7(2)16-13(14)17-11)6-9(12(19)20)10-4-5-15-18-10/h4-6H,3H2,1-2H3,(H,15,18)(H2,14,16,17)
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| Chemical Name |
2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7-one
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| Synonyms |
XL-765; XL765; XL 765; Voxtalisib; SAR 245409; SAR245409; SAR245409
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~54 mg/mL (199.78 mM)
Water: <1 mg/mL (slightly soluble or insoluble) Ethanol: <1 mg/mL (slightly soluble or insoluble) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1 mg/mL (3.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.6997 mL | 18.4986 mL | 36.9973 mL | |
| 5 mM | 0.7399 mL | 3.6997 mL | 7.3995 mL | |
| 10 mM | 0.3700 mL | 1.8499 mL | 3.6997 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00485719 | Completed | Drug: XL765 (SAR245409) | Cancer | Sanofi | June 2007 | Phase 1 |
| NCT01240460 | NCT01240460 | Drug: XL765 (SAR245409) Drug: XL147 (SAR245408) |
Glioblastoma Astrocytoma, Grade IV |
Sanofi | January 2011 | Phase 1 |
| NCT00704080 | Completed | Drug: Temozolomide Drug: XL765 (SAR245409) |
Mixed Gliomas Malignant Gliomas |
Sanofi | August 2008 | Phase 1 |
| NCT00777699 | Completed | Drug: Temozolomide Drug: XL765 (SAR245409) |
Mixed Gliomas Malignant Gliomas |
Sanofi | August 2008 | Phase 1 |
| NCT01410513 | Completed | Drug: SAR245409 | Mantle Cell Lymphoma | Sanofi | December 2011 | Phase 1 |
Mirzoeva OK, et al. J Mol Med, 2011, 89(9), 877-889. |
Mirzoeva OK, et al. J Mol Med, 2011, 89(9), 877-889. |
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