Everolimus (RAD001)

Catalog No.S1120

Everolimus (RAD001) is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM in a cell-free assay.

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Everolimus (RAD001) Chemical Structure

Everolimus (RAD001) Chemical Structure
Molecular Weight: 958.22

Validation & Quality Control

Cited by 49 publications:

5 customer reviews :

Quality Control & MSDS

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    Combination Therapy

Product Description

Biological Activity

Description Everolimus (RAD001) is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM in a cell-free assay.
Targets mTOR (FKBP12) [1]
(Cell-free assay)
IC50 1.6 nM-2.4 nM
In vitro Everolimus exhibits the immunosuppressive activity which is comparable to that of rapamycin. Everolimus competes with immobilized FK 506 for binding to biotinylated FKBP12 and shows the inhibitory effect on a two-way MLR performed with spleen cells from BALB/c and CBA mice with IC50 of 0.12-1.8 nM. [1] Everolimus also shows antiangiogenic/vascular effects in VEGF-induced HUVEC proliferation with IC50 of 0.12 nM and bFGF-induced HUVEC proliferation with IC50 of 0.8 nM, respectively. [2] A recent study shows that Everolimus shows a dose-dependent inhibitory effects on both the total cells and the stem cells from the BT474 cell line and the primary breast cancer cells with IC50 of 156 nM in total cells of primary breast cancer cells and 71 nM in total cells of BT474 cells. In addition, combination treatment with Everolimus and trastuzumab produces the significantly increased inhibition on the growth of cancer stem cells with the inhibition rate increased by more than 50 %. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
SQ20BMWXDfZRwfG:6aXOgRZN{[Xl?NHTxXI84OiCqNVLuVmt2TE2VTx?=MVTJR|UxRTVwNTFOwG0>MoHYNlQ1PDV|MUG=
Colo205MoD3R5l1d3SxeHnjJGF{e2G7Mke0O|IhcA>?NXf2WHFNTE2VTx?=MVfJR|UxRTJyIN88US=>M4XJTVI1PDR3M{Gx
ColoRNVS1TGRVS3m2b4TvfIlkKEG|c3H5M{H1UFczKGh?M3i2c2ROW09?Mo\oTWM2OD16Lkeg{txOMX2yOFQ1PTNzMR?=
HCT116MmDJR5l1d3SxeHnjJGF{e2G7NELINFQ4OiCqMlPuSG1UVw>?NX3hc2tYUUN3ME2xNkDPxE1?MWWyOFQ1PTNzMR?=
HT29NHnudmVEgXSxdH;4bYMhSXO|YYm=NUPBdIFCPzJiaB?=Mnq4SG1UVw>?MUjJR|UxRTF3IN88US=>NIWzc2IzPDR2NUOxNS=>
CAKI1MoDkR5l1d3SxeHnjJGF{e2G7NHnSSnY4OiCqNWraSYM{TE2VTx?=M4m5N2lEPTB;MUSg{txOM4fZUVI1PDR3M{Gx
SK-HEP1MmHDR5l1d3SxeHnjJGF{e2G7NYrQcIxVPzJiaB?=MXHEUXNQM1;EWmlEPTB;MUKg{txOMo[yNlQ1PDV|MUG=
DU145NWH3S2NIS3m2b4TvfIlkKEG|c3H5M1TY[lczKGh?NFu5TFBFVVORNGC2V4NKSzVyPUig{txONVnhNJVtOjR2NEWzNVE>
OVCAR3MWLDfZRwfG:6aXOgRZN{[Xl?MlS3O|IhcA>?M4jJZ2ROW09?MYTJR|UxRTF4IN88US=>MorDNlQ1PDV|MUG=
HOP62M2jZcWN6fG:2b4jpZ{BCe3OjeR?=NHniT5Y4OiCqM17KTmROW09?NITWZ3dKSzVyPUG5JO69VQ>?MnKyNlQ1PDV|MUG=
Colo205NH;2fHFHfW6ldHnvckBCe3OjeR?=MW[yOEBpMlvKSG1UVw>?M4nvR2lvcGmkaYTzJI1VV1KFMTDpckBpfW2jbjDDU2xQOjB3IHPlcIx{KGG|c3Xzd4VlKGG|IILl[JVkfGmxbjDv[kBUPiCyaH;zdIhwenmuYYTpc44h[XRiMD6xJJRwKDhidV2=NHPzS3czPDh|NkC3NC=>
Colo205NHTsXpJHfW6ldHnvckBCe3OjeR?=MXuyOEBpMXrEUXNQM{fxe2lvcGmkaYTzJI1VV1KFMTDpckBpfW2jbjDDU2xQOjB3IHPlcIx{KGG|c3Xzd4VlKGG|IILl[JVkfGmxbjDv[kA1NUWEUEGgdIhwe3Cqb4L5cIF1cW:wIHH0JFAvOSC2bzC4JJVOMWSyOFg{PjB5MB?=
SK-HEP1MVXGeY5kfGmxbjDBd5NigQ>?M3LNZVI1KGh?M{jlWmROW09?NU\SUIFEUW6qaXLpeJMhdVSRUlOxJIlvKGi3bXHuJHNMNUiHUEGgZ4VtdHNiYYPz[ZN{\WRiYYOgdoVlfWO2aX;uJI9nKFN4IIDoc5NxcG:{eXzheIlwdiCjdDCwMlEhfG9iODD1US=>MXmyOFg{PjB5MB?=
SK-HEP1M332c2Z2dmO2aX;uJGF{e2G7NX;kTGtsOjRiaB?=NUfXemxzTE2VTx?=NVHKdlhMUW6qaXLpeJMhdVSRUlOxJIlvKGi3bXHuJHNMNUiHUEGgZ4VtdHNiYYPz[ZN{\WRiYYOgdoVlfWO2aX;uJI9nKDRvRVLQNUBxcG:|cHjvdplt[XSrb36gZZQhOC5zIITvJFghfU1?NWG4eGszOjR6M{[wO|A>

... Click to View More Cell Line Experimental Data

In vivo Everolimus (0.1 to 10 mg/kg) dose-dependently inhibits growth of the primary (ear) and lymph node metastases of B16/BL6 melanoma, with decreased total number of vessels and reduced mature vessels. [2] In a xenograft animal model of BT474 stem cells, Everolimus shows significant reductions in mean tumor sizes (590.6 mm3), compared to the control group with a tumor size of 698 mm3. Furthermore, combination treatment with Everolimus and trastuzumab significantly decreases the xenograft tumor size (410.8 mm3) more than Everolimus treatment alone. [3]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

FKBP12 binding assay & Mixed lymphocyte reaction (MLR) FKBP12 binding assay: Binding to the FK 506 binding protein (FKBP12) is indirectly assessed by means of an ELISA-type competition assay. FK 506 is included in each individual experiment as a standard, and the inhibitory activity is expressed as relative IC50 compared to FK 506 (rIC50 = IC50 Everolimus/IC50 FK 506). Mixed lymphocyte reaction (MLR): The immunosuppressive activities of RAP and its derivatives are assessed in a two-way MLR, using spleen cells of BALB/c and CBA mice. RAP is included in each individual experiment as a standard, and the inhibitory activity is expressed as relative IC50 compared to RAP (rIC50 = IC50 Everolimus/IC50 RAP).

Cell Assay: [3]

Cell lines BT474 cell line and the primary breast cancer cells
Concentrations 0.001-10 μM
Incubation Time 24 hours
Method The 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction assay (MTT assay) is used to compare the effects of Everolimus or trastuzumab on total breast cancer cells and breast CSCs. The total cells and the stem cells from the BT474 cell line and the primary breast cancer cells are respectively seeded into 96-well plates with different concentrations of the drugs, with five wells for each concentration, and the cells are cultured at 37 °C with 5 % CO2 in an incubator for 24 hours. The concentrations of Everolimus are 1 nM, 10 nM, 100 nM, 1 μM and 10 μM, and the concentrations of trastuzumab are 0.5 μg/mL, 1 μg/mL, 10 μg/mL, 50 μg/mL, and 100 μg/mL. The combinatorial inhibitory effect of Everolimus and Trastuzumab on the in vitro growth of breast CSCs is examined by MTT assay as well using 10 μg/mL trastuzumab in combination of increasing concentrations of everolimus (1 nM, 10 nM, 100 nM and 1 μM). After drug treatment for 24 hours, 20 μL MTT [5 mg/mL in phosphate buffered saline (PBS)] is added to each well, and the cells are incubated at 37 °C with 5 % CO2 and saturated humidity for 4 hours. Following the subsequent removal of the supernatant, 150 μL dimethyl sulfoxide (DMSO) is added to each well, and the cells are vortexed for 10 minutes. The light absorbance (OD value) is measured for each well using an ELISA reader. Each experiment is repeated in triplicate, and dose–response curves are plotted. The probit software of the statistical software package SPSS 17.0 for Windows is used to calculate the inhibitory concentration (IC50) of Everolimus.

Animal Study: [3]

Animal Models Cultured BT474 stem cells are injected beneath the left breast pad of BALB/c nude mice.
Formulation Everolimus is dissolved in saline.
Dosages ≤2 mg/kg
Administration Administered via p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Sedrani R, et al. Transplant Proc, 1998, 30(5), 2192-2194.

[2] Lane HA, et al. Clin Cancer Res, 2009, 15(5), 1612-1622.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02811861 Not yet recruiting Renal Cell Carcinoma Eisai Inc. September 2016 Phase 3
NCT02724020 Not yet recruiting Clear-cell Metastatic Renal Cell Carcinoma Millennium Pharmaceuticals, Inc. June 2016 Phase 2
NCT02321501 Recruiting Head and Neck Cancer|Lung Cancer M.D. Anderson Cancer Center|Novartis June 2016 Phase 1
NCT02732119 Recruiting Breast Cancer Novartis Pharmaceuticals|Novartis June 2016 Phase 1|Phase 2
NCT02796157 Not yet recruiting Coronary Artery Disease Yonsei University June 2016 --

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Chemical Information

Download Everolimus (RAD001) SDF
Molecular Weight (MW) 958.22
Formula

C53H83NO14

CAS No. 159351-69-6
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 30 mg/mL (31.3 mM)
Ethanol 7 mg/mL (7.3 mM)
Water <1 mg/mL (<1 mM)
In vivo 30% Propylene glycol (dissolve first)+5% Tween 80+ddH2O 5mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine, rapamycin deriv

Customer Product Validation(5)


Click to enlarge
Rating
Source Cancer Cell 2012 21(2), 155-67. Everolimus (RAD001) purchased from Selleck
Method Western blotting
Cell Lines MP tumor cells
Concentrations 1, 5 uM
Incubation Time 3 h
Results To confirm that these compounds were acting on the PI3K/mTOR pathway, it performed western blotting to analyze phosphorylation of critical proteins in the pathway. As shown in figure, MP tumor cells showed substantial amounts of phospho-AKT and phospho-S6 in the absence of inhibitors (DMSO lanes). RAD-001 inhibited S6 phosphorylation but did not affect phospho-AKT. In contrast with RAD-001, treatment with BEZ-235 or BKM-120 inhibited phosphorylation of both AKT and S6.

Click to enlarge
Rating
Source Clin Cancer Res 2013 19(3),598-609. Everolimus (RAD001) purchased from Selleck
Method Immunoblotting
Cell Lines K028, M34, K029 cells
Concentrations 0.25, 0.5, 1 uM
Incubation Time 30 min
Results Treatment of the BRAFi-resistant melanoma cells with the mTOR inhibitor RAD001 did lead to substantial decrease of S6 phosphorylation in the 3 BRAFi-resistant lines K028PR, M34PR, and K029PR; however, such an inhibition failed to elicit any inhibitory effect on the expression of PD-L1.

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Rating
Source Biochem Pharmacol 2011 82, 216-226. Everolimus (RAD001) purchased from Selleck
Method Western blot
Cell Lines H1299 cells
Concentrations 5 μM
Incubation Time 48 h
Results RAD001 and other mTOR inhibitors decreased the levels of survivin protein, as assessed by Western blot analysis, without affecting the levels of other IAP members. In addition, combined treatment with sorafenib and mTOR inhibitor Rapamycin and RAD001 decreased survivin expression to a greater extent than treatment with either alone.

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Rating
Source Br J Cancer 2014 111(6), 1168-79. Everolimus (RAD001) purchased from Selleck
Method Fluorescent staining
Cell Lines 786-O SuR cells
Concentrations 1 uM
Incubation Time 24 h
Results Actin-based structures were revealed by phalloidin, whereas localisation of focal adhesion points was achieved by fluorescent staining of p-paxillin. β-actin and p-paxillin were well organised in untreated cells; instead, the RAD-001 treatment was able to mildly disassemble cytoskeleton organisation and focal adhesion points formation. These effects were much more evident with the combination treatment with NVP-LDE225.

Click to enlarge
Rating
Source Aging (Albany NY) 2012 4(2), 119-32. Everolimus (RAD001) purchased from Selleck
Method Fluorescence microscopy
Cell Lines HGPS fibroblast cells
Concentrations 0.1 uM
Incubation Time 30 min
Results To examine the effects on nuclear morphology, it labeled cells with an antibody for lamin A/C and an antibody specific for progerin. At least 200 randomly selected cells were scored by fluorescence microscopy for cells under each condition. The rapamycin or RAD001 treated HGPS cells exhibited a clear reduction in nuclear blebbin.

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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