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Purity: ≥98%
XL388 is a novel, highly potent, selective, oral, ATP-competitive inhibitor of mTOR (mammalian target of rapamycin) with potential antitumor activity. It exhibits 1000-fold selectivity for mTOR over phosphatidylinositol 3-kinase (PI3K) and inhibits mTOR with an IC50 of 9.9 nM. In vitro tests revealed strong antiproliferative activity, and in vivo tests revealed high antitumor efficacy. Positive pharmacokinetic characteristics and oral bioavailability of XL388 in various species are present. Significant tumor suppression effects were obtained when XL388 was administered orally to athymic nude mice bearing human tumor xenografts.
| Targets |
mTOR (IC50 = 9.9 nM); DNA-PK (IC50 = 8.831 μM); mTORC1; mTORC2
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| ln Vitro |
XL388 (Compound 28) also inhibits DNA-PK with an IC50 of 8.831 μM. XL388 inhibits cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. With a linear increase in IC50 values with rising ATP concentrations, XL388 behaves in an ATP-competitive manner[1]. In order to promote MG-63 cell apoptosis, XL388 exhibits a dose-dependent effect. The non-cancerous MC3T3-E1 cells are not affected by XL388 (100 nM), but the other two OS cell lines (U2OS and SaOs-2) are. In MG-63 cells, XL388 effectively inhibits the activation of mTORC1 and mTORC2. Once more, the dose-dependent nature of XL388's impact on mTORC1/2 activation. Additionally, mTORC1/2 activation is nearly blocked in U2OS cells, SaOs-2 cells, and primary human OS cells treated with XL388 (100 nM)[2].
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| ln Vivo |
Athymic nude mice bearing PC-3 prostate tumors are dosed orally with 100 mg/kg of XL388 (Compound 28) to examine the pharmacodynamic effects of XL388 on the mTOR pathway signaling. In addition, 5 mg/kg of rapamycin is administered intraperitoneally as a reference. Following dosing of XL388 and Rapamycin, plasma and tumor samples are obtained and homogenized with buffer at 1, 4, 8, 16, 24, and 32 h. The levels of phosphorylated p70S6K, S6, 4E-BP1, and AKT are then determined by immunoblotting tumor lysates from each animal (n=5) in each group. XL388 has a moderate terminal elimination half-life (t1/2=1.35 h, 0.45 h, 6.11 h, and 0.86 h for mouse (10 mg/kg,iv), rat (3 mg/kg,iv), dog (3 mg/kg,iv), monkey (3 mg/kg, iv))[1].
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| Enzyme Assay |
The 4E-BP1 protein is phosphorylated before the mTOR enzyme activity is measured using an ELISA format. Every experiment is run in a 384-well format. Typically, 15 mL of the enzyme solution is combined with 0.5 mL of DMSO containing the test compound in various concentrations. The addition of 15 L of a solution containing the substrate starts kinase reactions. The following are the assay conditions: In 20 mM Hepes, pH 7.2, 1 mM DTT, 50 mM NaCl, 10 mM MnCl2, 0.02 mg/mL BSA, 0.01% CHAPS, and 50 mM -glycerophophate, there are 0.2 nM mTOR, 10 nM ATP, and 50 nM NHis-tagged 4E-BP1.Following an incubation of 120 min at ambient temperature, 20 μL of the reaction mixture is transferred to a Ni-chelate-coated 384-well plate. The 4E-BP1 protein underwent a 60-minute binding process before being washed four times with 50 L of Tris-buffered saline solution (TBS). The reaction mixture is then supplemented with anti-phospho-4E-BP1 rabbit immunoglobulin G (IgG; 20 L, 1:5000) in 5% BSA-TBST (0.2% Tween-20 in TBS), and incubated for an additional 60 minutes. After the primary antibody has been removed (four washes of 50 L), a similar process is used to incubate a secondary anti-IgG that has been HP-tagged. 20 L of SuperSignal ELISA Femto are added after the last TBST wash, and the luminescence is then measured with an EnVision plate reader. The mean (n≥2) is used to represent data [1].
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| Cell Assay |
U2OS, SaOs-2 and MG-63 OS cell lines as well as the murine calvaria-derived osteoblastic MC3T3-E1 cells are maintained and culture. The OB-6 human osteoblastic cells are cultured. For primary culture of murine osteoblasts, the trimmed calvariae of neonatal mice are digested with 0.1% collagenase I and 0.25% dispase. The resolving cell suspensions are neutralized with complete culture medium and are filtered. The calvarial osteoblasts are then resuspended in 10 mL α-MEM containing 15% FBS, and are cultured. Cells (5×104/well) are suspended in 1 mL of DMEM with 1% agar, 10 % FBS and with indicated XL388 (5, 25, 100 and 200nM) treatment. The cell suspension is then added on top of a pre-solidified 1% agar in a 100 mm culture dish. The drug containing medium is refreshed every 2 days. After 10-day incubation, the number of remaining colonies are stained and manually counted[2].
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| Animal Protocol |
Mice, Rats, Dogs and Monkeys;[1]
Male beagle dogs, male cynomolgus monkeys, female CD rats, and female athymic nude mice are used in the pharmacokinetic studies of XL388. As a solution formulated in EPW (5% ethanol/45% PEG400/water+1:2 HCl (m/m)), XL388 is given intravenously and orally to male cynomolgus monkeys and CD rats at a dose of 10 mg/kg, 3 mg/kg, and 1.5 mg/kg, respectively. It is also given to male beagle dogs and CD rats at a dose of 3 mg/kg. Over the course of 24 hours, the plasma levels of XL388 are monitored. |
| References |
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| Additional Infomation |
mTORC1/mTORC2 Inhibitor XL388 is an orally bioavailable, ATP-competitive inhibitor of raptor-mammalian target of rapamycin (mTOR) complex 1 (mTOR complex 1; mTORC1; TOR complex 1; TORC1) and rictor-mTOR (mTOR complex 2; mTORC2; TOR complex 2; TORC2), with potential antineoplastic activity. Upon oral administration, mTORC1/mTORC2 inhibitor XL388 targets, selectively binds to and inhibits both mTORC1 and mTORC2, which may result in apoptosis and a decrease in proliferation in mTORC1/2-expressing tumor cells. mTOR is a serine/threonine kinase that is upregulated in some tumors; it plays an important role in the PI3K/Akt/mTOR signaling pathway which is often deregulated in cancer cells.
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| Molecular Formula |
C23H22N3O4FS
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|---|---|
| Molecular Weight |
455.50188
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| Exact Mass |
455.131
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| Elemental Analysis |
C, 60.65; H, 4.87; F, 4.17; N, 9.23; O, 14.05; S, 7.04
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| CAS # |
1251156-08-7
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| Related CAS # |
1251156-08-7
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| PubChem CID |
59604787
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
738.6±60.0 °C at 760 mmHg
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| Flash Point |
400.5±32.9 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
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| Index of Refraction |
1.619
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| LogP |
1.44
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
32
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| Complexity |
776
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(N1CCOC2=CC=C(C3=CC=C(N)N=C3)C=C2C1)C4=CC=C(S(=O)(C)=O)C(F)=C4C
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| InChi Key |
LNFBAYSBVQBKFR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H22FN3O4S/c1-14-18(5-7-20(22(14)24)32(2,29)30)23(28)27-9-10-31-19-6-3-15(11-17(19)13-27)16-4-8-21(25)26-12-16/h3-8,11-12H,9-10,13H2,1-2H3,(H2,25,26)
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| Chemical Name |
(7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)(3-fluoro-2-methyl-4-(methylsulfonyl)phenyl)methanone
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| Synonyms |
XL388; XL 388; XL-388
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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: ~23 mg/mL (50.5 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.49 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.5 mg/mL (5.49 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 25.0 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: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1954 mL | 10.9769 mL | 21.9539 mL | |
| 5 mM | 0.4391 mL | 2.1954 mL | 4.3908 mL | |
| 10 mM | 0.2195 mL | 1.0977 mL | 2.1954 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.
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