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Purity: ≥98%
Everolimus (formerly also known as RAD001, SDZ-RAD, or the 40-O-(2-hydroxyethyl) derivative of sirolimus) is a potent and orally bioavailable inhibitor of mammalian target of rapamycin (mTOR) with immunosuppressive activity. In a cell-free assay, it inhibits mTOR with an IC50 range of 1.6–2.4 nM. It forms an everolimus-FKBP12 complex by binding to the intracellular receptor FKBP12 in the mTOR pathway with high affinity. The complex also binds to mTOR, which inhibits the activity of downstream effectors S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP), as well as mTOR itself. Everolimus is sold as a transplantation drug under the trade names Zortress (USA) and Certican (EU and other countries), and for oncological uses as Afinitor (general tumors) and Votubia (tumours resulting from TSC).
| Targets |
mTOR (IC50 = 5-6 nM)
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|---|---|
| ln Vitro |
Everolimus (RAD001) is an orally active derivative of rapamycin that inhibits the Ser/Thr kinase, mTOR[1]. Antiproliferative concentrations of Everolimus cause total dephosphorylation of S6K1 and the substrate S6 in both the sensitive murine B16/BL6 melanoma (IC50, 0.7 nM) and the insensitive human cervical KB-31 (IC50, 1,778 nM) as well as a shift in the mobility of 4E-BP1, which is suggestive of a reduced phosphorylation status[3]. Although to varying degrees, everolimus inhibits the growth of both the total cells, the stem cells, and the primary breast cancer cells from the BT474 cell line. Everolimus is less effective at inhibiting stem cell growth at all tested concentrations when compared to the total number of cells (P<0.001). Everolimus has an IC50 for BT474 and primary CSCs of 2,054 and 3,227 nM, respectively, which is 29 and 21 times greater than the IC50 for the corresponding total cells[4].
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| ln Vivo |
Everolimus is orally active in both mice and rats, producing an antitumor effect that is characterized by dramatic reduction in tumor growth rates as opposed to producing tumor regressions. Everolimus (0.5 or 2.5 mg/kg) daily treatment inhibits tumor growth in the rat CA20498 model in a dose-dependent manner, and intermittent administration of a higher dose of 5 mg/kg (once or twice per week) also exhibits comparable antitumor efficacy. Everolimus inhibition is not accompanied by any loss of body weight and is characterized by sustained suppression as opposed to regression[1]. Everolimus treatment (0.1–10 mg/kg/d) has a selective effect that is different from PTK/ZK treatment (100 mg/kg). Everolimus increases hemoglobin content, which is a measure of the number of vessels and their leakiness when converted to blood equivalents, when either growth factor is present. However, Everolimus decreases Tie-2 content, which is significant for VEGF stimulation but not bFGF stimulation. According to the pharmacokinetics of Everolimus in mice, plasma levels only reach 1 to 3 μM for about 4 hours while maximum levels of only 0.1 M are found in a human tumor xenograft after a single administration[3].
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| Enzyme Assay |
FKBP12 binding assay: An ELISA-xstyle competition assay is used to inadvertently measure binding to the FK 506 binding protein (FKBP12). Each experiment uses FK 506 as a standard, and the inhibitory activity is expressed as a relative IC50 (rIC50 = IC50 Everolimus/IC50 FK 506) in comparison to FK 506. Using the spleen cells from BALB/c and CBA mice, the immunosuppressive effects of RAP and its derivatives are examined in a two-way mixed lymphocyte reaction (MLR). Since RAP serves as a standard in each experiment, the inhibitory activity is expressed as a relative IC50 (rIC50 = IC50 Everolimus/IC50 RAP) in comparison to RAP.
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| Cell Assay |
In 96-well plates, tumor cells are plated at densities ranging from 500 to 5,000/100 μL/well. Repeat experiments are then carried out with an optimal cell density, typically 1,000 to 2,000 cells per well, and incubated overnight. Methylene blue staining is used to count the cells after they have been exposed to Everolimus and incubated for 4 days. To do this, wells are filled with 50 μL of [20% (v/v)] glutaraldehyde and left to sit for 10 minutes at room temperature. Incubate 100 L of methylene blue [0.05% (w/v) in water] for 10 minutes at 37°C after aspirating the culture medium, washing the cells with distilled water, and adding the dye.
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| Animal Protocol |
Mice: Everolimus, PTK/ZK, and their respective vehicles are prepared each day just before administration to animals and the administration volume is individually adjusted based on animal body weight. Everolimus is given to C57/BL6 mice at doses ranging from 0.1 to 10 mg/kg/d orally (10 mL/kg), with 2.5 to 10 mg/kg being the most frequently used dose because it has the greatest impact. PTK/ZK is given orally at a dose of 50 to 100 mg/kg/d.
Rats: Based on body weight, Wistar-Furth rats are divided into two equal groups and given either a control dose of the drug or Everolimus (10 mg/kg/d orally in mice and 5 mg/kg three times per week orally in rats). Everolimus or vehicle is given orally by gavage (10 mL/kg) for a maximum of 7 days, with subsequent magnetic resonance measurements taken within 30 minutes of the last dose. This is done immediately after the initial measurement at baseline (day 0). |
| References |
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| Molecular Formula |
C53H83NO14
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|---|---|
| Molecular Weight |
958.22
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| Exact Mass |
957.58136
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| Elemental Analysis |
C, 66.43; H, 8.73; N, 1.46; O, 23.38
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| CAS # |
159351-69-6
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| Related CAS # |
Everolimus-d4;1338452-54-2
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| Appearance |
White to off-white solid powder
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| SMILES |
O=C(C(N1CCCC[C@@]1([H])C(O[C@H]([C@H](C)C[C@H]2C[C@@H](OC)[C@H](OCCO)CC2)CC([C@H](C)/C=C(C)/[C@@H](O)[C@H]3OC)=O)=O)=O)[C@@](O4)(O)[C@H](C)CC[C@@]4([H])C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C3=O
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| InChi Key |
HKVAMNSJSFKALM-GKUWKFKPSA-N
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| InChi Code |
InChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1
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| Chemical Name |
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta16,24,26,28-tetraene-2,3,10,14,20-pentaone.
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| Synonyms |
SDZ-RAD; RAD-001; RAD001; RAD 001; Everolimus; Brand name Afinitor; Certican; Zortress; Xience V; Zortress
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.61 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 (2.61 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), suspension solution; with ultrasonication. 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: ≥ 2.5 mg/mL (2.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2.5 mg/mL (2.61 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: 2.5 mg/mL (2.61 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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. Solubility in Formulation 6: 30% Propylene glycol (dissolve first)+5% Tween 80+ddH2O: 5 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0436 mL | 5.2180 mL | 10.4360 mL | |
| 5 mM | 0.2087 mL | 1.0436 mL | 2.0872 mL | |
| 10 mM | 0.1044 mL | 0.5218 mL | 1.0436 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 | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01141309 | Active Recruiting |
Drug: sorafenib with everolimus | Thyroid Cancer | Memorial Sloan Kettering Cancer Center | June 2010 | Phase 2 |
| NCT03070301 | Active Recruiting |
Drug: LEE011 Drug: everolimus |
Neuroendocrine Tumors | Memorial Sloan Kettering Cancer Center | February 27, 2017 | Phase 2 |
| NCT05501769 | Recruiting | Drug: ARV-471 in combination with Everolimus |
Drug Evaluation Breast Cancer |
Arvinas Estrogen Receptor, Inc. | September 8, 2022 | Phase 1 |
| NCT05153668 | Recruiting | Drug: Everolimus Oral Tablet | Idiopathic Subglottic Tracheal Stenosis |
Johns Hopkins University | September 30, 2022 | Early Phase 1 |
| NCT05252585 | Recruiting | Drug: Everolimus | Renal Angiomyolipoma | Novartis Pharmaceuticals | May 1, 2023 | Phase 4 |
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