Drug Details

General Information of the Drug (ID: DR7612)
Name
Everolimus
Synonyms
001, RAD; 40-O-(2-hydroxyethyl)-rapamycin; 40-O-(2-Hydroxyethyl)rapamycin; Afinitor; Certican; Everolimus; RAD; RAD 001; RAD, SDZ; RAD001; SDZ RAD; SDZ-RAD; Zortress; 42-O-(2-Hydroxyethyl)rapamycin; 159351-69-6; Votubia; Afinitor Disperz; CHEBI:68478; RAD-001; UNII-9HW64Q8G6G; 9HW64Q8G6G; NCGC00167512-01; Rapamycin, 42-O-(2-hydroxyethyl)-; (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-3-{(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone; (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,35R)-1,18-dihydroxy-12-{(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone; everolimusum; NSC733504; Everolimus solution; Everolimus (INN); SDZRAD; XIENCE V; PubChem20048; Everolimus - RAD001; SCHEMBL4378; DSSTox_CID_20599; DSSTox_RID_79508; NVP-RAD001; DSSTox_GSID_40599; Everolimus [USAN:INN:BAN]; NVP-RAD-001; Everolimus, analytical standard; GTPL5889; RAD-001C; CHEMBL1908360; DTXSID0040599; HSDB 8255; RAD 666; RAD-666; Everolimus; RAD001; SDZ-RAD; C53H83NO14; 42-O-(2-Hydroxyethyl)-rapamycin; EX-A2057; Tox21_112510; BDBM50088378; AKOS015850977; ZINC169677008; CS-0064; DB01590; (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-(2-hydroxyethoxy)-3-methoxycyclohexyl)-1-methylethyl)-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo(30.3.1.0(sup 4,9))hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone; (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-(2-hydroxyethoxy)-3-methoxycyclohexyl)-1-methylethyl)-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo(30.3.1.04,9)hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone; (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-((1R)-2-((1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl)-1-methylethyl)-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido(2,1-c)(1,4)oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone; AS-16971; AT-22180; HY-10218; CAS-159351-69-6; V2036; Everolimus solution, 1.0 mg/ml in acetonitrile; 351E696; Q421052; Q-101413; BRD-K13514097-001-01-2; BRD-K13514097-001-05-3; dihydroxy-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxy-cyclohexyl]-1-methyl-ethyl]-dimethoxy-hexamethyl-[?]pentone; Everolimus solution, 1.0 mg/mL in acetonitrile, ampule of 1 mL, certified reference material
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Molecular Type
Small molecule
Disease Renal cell carcinoma [ICD-11: 2C90] Approved [1]
Structure
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2D MOL

3D MOL

ADMET Property
BDDCS Class
Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability
Elimination
0% of drug is excreted from urine in the unchanged form
Half-life
The concentration or amount of drug in body reduced by one-half in 30 hours
MRTD
The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.1491 micromolar/kg/day
Water Solubility
The ability of drug to dissolve in water is measured as 0.01 mg/mL
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    Click to Show/Hide the Molecular Information and External Link(s) of This Natural Product
Formula
C53H83NO14
PubChem CID
6442177
Canonical SMILES
CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)OCCO)C)C)O)OC)C)C)C)OC
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
InChIKey
HKVAMNSJSFKALM-GKUWKFKPSA-N
CAS Number
CAS 159351-69-6
ChEBI ID
CHEBI:68478
TTD Drug ID
D0K3QS
DrugBank ID
DB01590
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Natural Product(s) Able to Enhance the Efficacy of This Drug
          Arsenic trioxide      Realgar and orpiment     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Expression MAP1LC3A  Molecule Info 
Pathway MAP
Up-regulation Cleavage PARP1  Molecule Info 
Pathway MAP
                    In-vitro Model SK-OV-3 CVCL_0532 Ovarian serous cystadenocarcinoma Homo sapiens
LNCaP CVCL_0395 Prostate carcinoma Homo sapiens
                    In-vivo Model Six-week-old SCID (severe combined immuno deficiency) mice were inoculated with 100 ul (50% Matrigel/PBS) LNCaP cells suspension (6 * 106) to either dorsal flank with 25-gauge syringe.
                    Experimental
                    Result(s)		 Combination of Arsenic trioxide and Everolimus (Rad001) synergistically induces both autophagy and apoptosis in prostate cancer cells.
          Metformin      Galega officinalis     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression mTOR  Molecule Info 
Pathway MAP
                    In-vitro Model HCC1428 CVCL_1252 Breast adenocarcinoma Homo sapiens
MDA-MB-468 CVCL_0419 Breast adenocarcinoma Homo sapiens
BT-549 CVCL_1092 Invasive breast carcinoma Homo sapiens
                    In-vivo Model HCC1428 cells (1.0*106) were injected subcutaneously into the abdominal mammary fat pads of female BALB/c-nu mice.
                    Experimental
                    Result(s)		 Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models.
          Paroxetine      Areca catechu     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model SH-SY5Y CVCL_0019 Neuroblastoma Homo sapiens
                    Experimental
                    Result(s)		 Combination treatment with Everolimus and Paroxetine showed synergistic post-ischemic neuroprotective efficacy.
    β. A List of Natural Product(s) Able to Decrease the Adverse Effect of This Drug
          Mycophenolate mofetil      Penicillium stoloniferum     Click to Show/Hide the Molecular Data of This NP
                 Decreasing Adverse Drug Reaction     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vivo Model Clinical Trial
                    Experimental
                    Result(s)		 This regimen was proven to be efficient to prevent and treat nephrotoxicity and neurotoxicity with an acceptable tolerability profile.
    γ. A List of Natural Product(s) Able to Reverse the Resistance of This Drug
          Sulforaphane      Brassica oleracea     Click to Show/Hide the Molecular Data of This NP
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression CCNB1  Molecule Info 
Pathway MAP
Down-regulation Expression CDK1  Molecule Info 
Pathway MAP
Up-regulation Expression IFI27  Molecule Info 
Pathway MAP
Up-regulation Expression REG1A  Molecule Info 
Pathway MAP
                    In-vitro Model RT-112 CVCL_1670 Bladder carcinoma Homo sapiens
UM-UC-3 CVCL_1783 Bladder carcinoma Homo sapiens
TCCSUP CVCL_1738 Bladder carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Chronic sulforaphane administration inhibits resistance to the mTOR-inhibitor everolimus in bladder cancer cells.
Target and Pathway
Target(s) Serine/threonine-protein kinase mTOR (mTOR)  Molecule Info  [7]
KEGG Pathway ErbB signaling pathway Click to Show/Hide
2 HIF-1 signaling pathway
3 mTOR signaling pathway
4 PI3K-Akt signaling pathway
5 AMPK signaling pathway
6 Insulin signaling pathway
7 Thyroid hormone signaling pathway
8 Adipocytokine signaling pathway
9 Type II diabetes mellitus
10 Pathways in cancer
11 Proteoglycans in cancer
12 MicroRNAs in cancer
13 Glioma
14 Prostate cancer
15 Acute myeloid leukemia
16 Central carbon metabolism in cancer
17 Choline metabolism in cancer
Panther Pathway Hypoxia response via HIF activation Click to Show/Hide
2 Interleukin signaling pathway
Pathwhiz Pathway Leucine Stimulation on Insulin Signaling Click to Show/Hide
Pathway Interaction Database IL4-mediated signaling events Click to Show/Hide
2 Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
3 IL12-mediated signaling events
4 CDC42 signaling events
5 LKB1 signaling events
6 Regulation of Telomerase
7 mTOR signaling pathway
8 CXCR4-mediated signaling events
9 EGFR-dependent Endothelin signaling events
10 IL2 signaling events mediated by PI3K
11 IFN-gamma pathway
12 ErbB1 downstream signaling
13 ErbB2/ErbB3 signaling events
14 CXCR3-mediated signaling events
15 Class I PI3K signaling events mediated by Akt
Reactome PIP3 activates AKT signaling Click to Show/Hide
2 Macroautophagy
3 mTORC1-mediated signalling
4 HSF1-dependent transactivation
5 CD28 dependent PI3K/Akt signaling
6 VEGFR2 mediated vascular permeability
7 TP53 Regulates Metabolic Genes
8 Constitutive Signaling by AKT1 E17K in Cancer
WikiPathways ErbB Signaling Pathway Click to Show/Hide
2 Senescence and Autophagy in Cancer
3 Interferon type I signaling pathways
4 Insulin Signaling
5 EGF/EGFR Signaling Pathway
6 Wnt Signaling Pathway Netpath
7 Extracellular vesicle-mediated signaling in recipient cells
8 Cardiac Hypertrophic Response
9 Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
10 PIP3 activates AKT signaling
11 Polycystic Kidney Disease Pathway
12 Alpha 6 Beta 4 signaling pathway
13 BDNF signaling pathway
14 Oncostatin M Signaling Pathway
15 Prostate Cancer
16 TSLP Signaling Pathway
17 FSH signaling pathway
18 Leptin signaling pathway
19 TSH signaling pathway
20 RANKL/RANK Signaling Pathway
21 SREBF and miR33 in cholesterol and lipid homeostasis
22 Integrated Breast Cancer Pathway
23 SREBP signalling
24 Signaling by Insulin receptor
25 Costimulation by the CD28 family
26 Type II diabetes mellitus
27 MicroRNAs in cardiomyocyte hypertrophy
28 TOR Signaling
29 AMPK Signaling
References
Reference 1 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5889).
Reference 2 Combination of Arsenic trioxide and Everolimus (Rad001) synergistically induces both autophagy and apoptosis in prostate cancer cells. Oncotarget. 2017 Feb 14;8(7):11206-11218.
Reference 3 Combined Use of Metformin and Everolimus Is Synergistic in the Treatment of Breast Cancer Cells. Oncol Res. 2014;22(4):193-201.
Reference 4 The Synergistic Combination of Everolimus and Paroxetine Exerts Post-ischemic Neuroprotection In Vitro. Cell Mol Neurobiol. 2018 Oct;38(7):1383-1397.
Reference 5 Everolimus plus mycophenolate mofetil as initial immunosuppression in liver transplantation. Transplant Proc. Jan-Feb 2015;47(1):90-2.
Reference 6 Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells. Int J Mol Sci. 2020 Jun 4;21(11):4026.
Reference 7 Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9.
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