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Identification
- Summary
Everolimus is a mammalian target of rapamycin (mTOR) kinase inhibitor used to treat various types of malignancies.
- Brand Names
- Afinitor, Torpenz, Votubia, Zortress
- Generic Name
- Everolimus
- DrugBank Accession Number
- DB01590
- Background
Everolimus is a derivative of Rapamycin (sirolimus), and works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. In a similar fashion to other mTOR inhibitors Everolimus' effect is solely on the mTORC1 protein and not on the mTORC2 protein.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Everolimus (DB01590)
- Weight
- Average: 958.24
Monoisotopic: 957.581356357 - Chemical Formula
- C53H83NO14
- Synonyms
- 40-O-(2-hydroxyethyl)-rapamycin
- 42-O-(2-Hydroxyethyl)rapamycin
- Everolimus
- évérolimus
- External IDs
- RAD 666
- RAD-001
- RAD-666
- RAD001
- SDZ RAD
- SDZ-RAD
Pharmacology
- Indication
Everolimus is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. Indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination for prophylaxis of Heart transplant rejection ••• ••••• Used as adjunct in combination to prevent Kidney transplant rejection Regimen in combination with: Basiliximab (DB00074), Cyclosporine (DB00091) •••••••••••• ••••• Used as adjunct in combination to prevent Liver transplant rejection Regimen in combination with: Tacrolimus (DB00864) •••••••••••• ••••• Treatment of Renal angiomyolipoma, tuberous sclerosis complex •••••••••••• ••••• Treatment of Subependymal giant cell astrocytoma, tuberous sclerosis complex •••••••••••• •••••• ••••••••• - Contraindications & Blackbox Warnings
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Not Available
- Mechanism of action
Everolimus is a mTOR inhibitor that binds with high affinity to the FK506 binding protein-12 (FKBP-12), thereby forming a drug complex that inhibits the activation of mTOR. This inhibition reduces the activity of effectors downstream, which leads to a blockage in the progression of cells from G1 into S phase, and subsequently inducing cell growth arrest and apoptosis. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of vascular endothelial growth factor. The result of everolimus inhibition of mTOR is a reduction in cell proliferation, angiogenesis, and glucose uptake.
Target Actions Organism ASerine/threonine-protein kinase mTOR inhibitorHumans - Absorption
In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing. Dose Proportionality in Patients with SEGA (subependymal giant-cell astrocytomas) and TSC (tuberous sclerosis complex): In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.
- Volume of distribution
The blood-to-plasma ratio of everolimus is 17% to 73%.
- Protein binding
~ 74% in both healthy patients and those with moderate hepatic impairment.
- Metabolism
Everolimus is a substrate of CYP3A4 and PgP (phosphoglycolate phosphatase). Three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus were the 6 primary metabolites detected in human blood. In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan.
- Route of elimination
After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine.
- Half-life
~30 hours.
- Clearance
Following a 3 mg radiolabeled dose of everolimus, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine.
- Adverse Effects
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IC50 of 0.63 nM.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Everolimus can be increased when it is combined with Abametapir. Abatacept The metabolism of Everolimus can be increased when combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Everolimus. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Everolimus. Abrocitinib The serum concentration of Everolimus can be increased when it is combined with Abrocitinib. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits the metabolism of everolimus through the CYP3A4 pathway and, therefore, may increase serum levels of everolimus.
- Avoid St. John's Wort. Coadministration of St. John's Wort with everolimus may reduce serum levels of everolimus by inducing CYP3A4 and P-glycoprotein (PGP).
- Take at the same time every day.
- Take with a full glass of water.
- Take with or without food. Take consistently with regard to food as food may reduce the AUC and Cmax of everolimus.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Afinitor Tablet 7.5 mg/1 Oral Novartis Farma S.P.A. 2011-07-29 Not applicable US 
Afinitor Tablet 5 mg/1 Oral Novartis Farma S.P.A. 2009-03-31 Not applicable US Afinitor Tablet 2.5 mg Oral Novartis Europharm Limited 2016-09-08 Not applicable EU 
Afinitor Tablet 10 mg Oral Novartis 2010-01-19 Not applicable Canada 
Afinitor Tablet 10 mg Oral Novartis Europharm Limited 2016-09-08 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Everolimus Tablet 5 mg/1 Oral Hikma Pharmaceuticals USA Inc. 2020-06-08 Not applicable US Everolimus Tablet 1 mg/1 Oral ENDO USA, Inc. 2022-01-26 Not applicable US Everolimus Tablet 5 mg/1 Oral Northstar RxLLC 2024-10-01 Not applicable US Everolimus Tablet, for suspension 5 mg/1 Oral Mylan Pharmaceuticals Inc. 2021-10-01 Not applicable US Everolimus Tablet 0.5 mg/1 Oral Breckenridge Pharmaceutical, Inc. 2021-05-21 Not applicable US
Categories
- ATC Codes
- L01EG02 — Everolimus
- L01EG — Mammalian target of rapamycin (mTOR) kinase inhibitors
- L01E — PROTEIN KINASE INHIBITORS
- L01 — ANTINEOPLASTIC AGENTS
- L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
- Drug Categories
- Anti-Bacterial Agents
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cancer immunotherapy
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Decreased Immunologic Activity
- Enzyme Inhibitors
- Hyperglycemia-Associated Agents
- Immunologic Factors
- Immunosuppressive Agents
- Immunotherapy
- Kinase Inhibitor
- Lactones
- Macrolides
- Mammalian target of rapamycin (mTOR) kinase inhibitors
- mTOR Inhibitor Immunosuppressant
- mTOR Inhibitors
- Myelosuppressive Agents
- Narrow Therapeutic Index Drugs
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B3 inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Polyketides
- Protein Kinase Inhibitors
- Selective Immunosuppressants
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Macrolide lactams
- Sub Class
- Not Available
- Direct Parent
- Macrolide lactams
- Alternative Parents
- Alpha amino acid esters / Macrolides and analogues / Piperidines / Oxanes / Tertiary carboxylic acid amides / Secondary alcohols / Carboxylic acid esters / Cyclic ketones / Hemiacetals / Lactams show 10 more
- Substituents
- Alcohol / Aliphatic heteropolycyclic compound / Alpha-amino acid ester / Alpha-amino acid or derivatives / Azacycle / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Carboxylic acid ester / Cyclic ketone show 23 more
- Molecular Framework
- Aliphatic heteropolycyclic compounds
- External Descriptors
- cyclic ketone, secondary alcohol, ether, primary alcohol, lactam, macrocyclic lactone, cyclic acetal (CHEBI:68478)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 9HW64Q8G6G
- CAS number
- 159351-69-6
- InChI Key
- HKVAMNSJSFKALM-GKUWKFKPSA-N
- InChI
- 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
- IUPAC Name
- (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,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[30.3.1.0⁴,⁹]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
- SMILES
- [H][C@@]1(C[C@@H](C)[C@]2([H])CC(=O)[C@H](C)\C=C(C)\[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(C)\[C@H](C[C@]3([H])CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@@]3([H])C(=O)O2)OC)CC[C@@H](OCCO)[C@@H](C1)OC
References
- Synthesis Reference
- General References
- Kuhn B, Jacobsen W, Christians U, Benet LZ, Kollman PA: Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations. J Med Chem. 2001 Jun 7;44(12):2027-34. [Article]
- Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010 Nov 4;363(19):1801-11. doi: 10.1056/NEJMoa1001671. [Article]
- den Burger JC, Wilhelm AJ, Chahbouni A, Vos RM, Sinjewel A, Swart EL: Analysis of cyclosporin A, tacrolimus, sirolimus, and everolimus in dried blood spot samples using liquid chromatography tandem mass spectrometry. Anal Bioanal Chem. 2012 Oct;404(6-7):1803-11. doi: 10.1007/s00216-012-6317-8. Epub 2012 Aug 17. [Article]
- Pawaskar DK, Straubinger RM, Fetterly GJ, Hylander BH, Repasky EA, Ma WW, Jusko WJ: Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice. Cancer Chemother Pharmacol. 2013 May;71(5):1231-40. doi: 10.1007/s00280-013-2117-x. Epub 2013 Mar 3. [Article]
- External Links
- KEGG Drug
- D02714
- PubChem Compound
- 6442177
- PubChem Substance
- 46505248
- ChemSpider
- 21106307
- BindingDB
- 50088378
- 141704
- ChEBI
- 68478
- ChEMBL
- CHEMBL1908360
- ZINC
- ZINC000169677008
- Therapeutic Targets Database
- DAP001223
- PharmGKB
- PA164746311
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Everolimus
- FDA label
- Download (548 KB)
- MSDS
- Download (220 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Available Not Available Uterine Sarcoma 1 somestatus stop reason just information to hide Not Available Completed Not Available Breast Cancer 1 somestatus stop reason just information to hide Not Available Completed Not Available Breast Cancer / Renal Cell Carcinoma (RCC) 1 somestatus stop reason just information to hide Not Available Completed Not Available Cardiovascular Disease (CVD) / Infarction / Myocardial Infarction / Necrosis / ST Segment Elevation Myocardial Infarction (STEMI) / Vascular Diseases 1 somestatus stop reason just information to hide Not Available Completed Not Available Function of Renal Transplant 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Chunghwa Chemical Synthesis and Biotech Co. Ltd.
- Novartis AG
- Quality Care
- Dosage Forms
Form Route Strength Tablet Oral Tablet Oral 10 mg/1 Tablet Oral 10.000 mg Tablet Oral 7.5 mg Tablet Oral 10 mg Tablet, soluble Oral 2 mg Tablet, soluble Oral 3 mg Tablet, soluble Oral 5 mg Tablet Oral 5 mg Tablet, for suspension Oral 2 mg/1 Tablet, for suspension Oral 2 mg Tablet, for suspension Oral 3 mg/1 Tablet, for suspension Oral 3 mg Tablet, for suspension Oral 5 mg/1 Tablet, for suspension Oral 5 mg Tablet Oral 10.00 mg Tablet Oral 5.00 mg Tablet Oral 0.250 mg Tablet Oral 0.50 mg Tablet, orally disintegrating Oral 0.1 mg Tablet Oral 0.5 mg Tablet, soluble Oral 0.25 mg Tablet Oral 0.25 mg Tablet Oral 0.75 mg Tablet Oral 1 mg Tablet, for suspension Oral Tablet, for suspension Oral 0.1 MG Tablet, for suspension Oral 0.25 MG Tablet Oral 0.1 mg Tablet Oral .25 mg/1 Tablet Oral .5 mg/1 Tablet Oral .75 mg/1 Tablet Oral 0.50 mg/1 Tablet Oral 2.5 mg/1 Tablet Oral 5 mg/1 Tablet Oral 7.5 mg/1 Tablet Oral 2.5 MG Tablet, for suspension Oral 1 MG Tablet, orally disintegrating Oral 2 mg Tablet, orally disintegrating Oral 3 mg Tablet, orally disintegrating Oral 5 mg Tablet Oral 0.25 mg/1 Tablet Oral 0.5 mg/1 Tablet Oral 0.75 mg/1 Tablet Oral 1 mg/1 - Prices
Unit description Cost Unit Afinitor 10 mg tablet 247.58USD tablet Afinitor 5 mg tablet 234.75USD tablet Vesicare 10 mg tablet 6.98USD tablet Vesicare 5 mg tablet 6.98USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US6440990 No 2002-08-27 2013-09-24 US CA2145383 No 2004-11-16 2013-09-24 Canada CA2225960 No 2004-05-11 2016-07-12 Canada US8410131 Yes 2013-04-02 2026-05-01 US US8436010 Yes 2013-05-07 2022-08-22 US US5665772 Yes 1997-09-09 2020-03-09 US US6004973 Yes 1999-12-21 2017-01-12 US US6239124 Yes 2001-05-29 2018-02-11 US US6455518 Yes 2002-09-24 2018-01-29 US US8778962 Yes 2014-07-15 2022-08-18 US US9006224 No 2015-04-14 2028-07-01 US US7741338 No 2010-06-22 2019-12-06 US US7297703 Yes 2007-11-20 2020-06-06 US US8617598 Yes 2013-12-31 2023-03-27 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00163 mg/mL ALOGPS logP 5.01 ALOGPS logP 7.4 Chemaxon logS -5.8 ALOGPS pKa (Strongest Acidic) 9.96 Chemaxon pKa (Strongest Basic) -2.7 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 13 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 204.66 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 261.71 m3·mol-1 Chemaxon Polarizability 106.61 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.8288 Blood Brain Barrier - 0.9541 Caco-2 permeable - 0.6604 P-glycoprotein substrate Substrate 0.8117 P-glycoprotein inhibitor I Inhibitor 0.7789 P-glycoprotein inhibitor II Inhibitor 0.7294 Renal organic cation transporter Non-inhibitor 0.796 CYP450 2C9 substrate Non-substrate 0.8793 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Substrate 0.7407 CYP450 1A2 substrate Non-inhibitor 0.9078 CYP450 2C9 inhibitor Non-inhibitor 0.9106 CYP450 2D6 inhibitor Non-inhibitor 0.9388 CYP450 2C19 inhibitor Non-inhibitor 0.9346 CYP450 3A4 inhibitor Non-inhibitor 0.8168 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9734 Ames test Non AMES toxic 0.6227 Carcinogenicity Non-carcinogens 0.9362 Biodegradation Not ready biodegradable 0.9257 Rat acute toxicity 2.7442 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9776 hERG inhibition (predictor II) Non-inhibitor 0.712
Spectra
- Mass Spec (NIST)
- Download (87.7 KB)
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 323.4346105 predictedDarkChem Lite v0.1.0 [M-H]- 305.66876 predictedDeepCCS 1.0 (2019) [M+H]+ 322.3908105 predictedDarkChem Lite v0.1.0 [M+H]+ 307.39243 predictedDeepCCS 1.0 (2019) [M+Na]+ 322.5953105 predictedDarkChem Lite v0.1.0 [M+Na]+ 313.72137 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084, PubMed:29150432, PubMed:29236692, PubMed:31112131, PubMed:31601708, PubMed:32561715, PubMed:34519269, PubMed:37751742). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins (PubMed:15268862, PubMed:15467718, PubMed:17517883, PubMed:18372248, PubMed:18497260, PubMed:18925875, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704, PubMed:29236692, PubMed:37751742). Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18497260, PubMed:18925875, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). In response to nutrients, growth factors or amino acids, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084, PubMed:29150432, PubMed:29236692, PubMed:31112131, PubMed:34519269). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (PubMed:24403073, PubMed:29236692). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12087098, PubMed:12150925, PubMed:18925875, PubMed:29150432, PubMed:29236692). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429703, PubMed:23429704). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). Activates dormant ribosomes by mediating phosphorylation of SERBP1, leading to SERBP1 inactivation and reactivation of translation (PubMed:36691768). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (PubMed:23426360). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). In the same time, mTORC1 inhibits catabolic pathways: negatively regulates autophagy through phosphorylation of ULK1 (PubMed:32561715). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (PubMed:32561715). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (PubMed:12150925, PubMed:12150926, PubMed:24403073, PubMed:31695197). The non-canonical mTORC1 complex, which acts independently of RHEB, specifically mediates phosphorylation of MiT/TFE factors MITF, TFEB and TFE3 in the presence of nutrients, promoting their cytosolic retention and inactivation (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670, PubMed:36697823). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670). The mTORC1 complex regulates pyroptosis in macrophages by promoting GSDMD oligomerization (PubMed:34289345). MTOR phosphorylates RPTOR which in turn inhibits mTORC1 (By similarity). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). mTORC2 plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity)
- Specific Function
- ATP binding
- Gene Name
- MTOR
- Uniprot ID
- P42345
- Uniprot Name
- Serine/threonine-protein kinase mTOR
- Molecular Weight
- 288889.05 Da
References
- Ettenger R, Hoyer PF, Grimm P, Webb N, Loirat C, Mahan JD, Mentser M, Niaudet P, Offner G, Vandamme-Lombaerts R, Hexham JM: Multicenter trial of everolimus in pediatric renal transplant recipients: results at three year. Pediatr Transplant. 2008 Jun;12(4):456-63. doi: 10.1111/j.1399-3046.2007.00832.x. [Article]
- Rostaing L, Kamar N: mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? J Nephrol. 2010 Mar-Apr;23(2):133-42. [Article]
- George S, Bukowski RM: Role of everolimus in the treatment of renal cell carcinoma. Ther Clin Risk Manag. 2009 Oct;5(5):699-706. Epub 2009 Sep 15. [Article]
- Teachey DT, Grupp SA, Brown VI: Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br J Haematol. 2009 Jun;145(5):569-80. doi: 10.1111/j.1365-2141.2009.07657.x. Epub 2009 Mar 16. [Article]
- Albert S, Serova M, Dreyer C, Sablin MP, Faivre S, Raymond E: New inhibitors of the mammalian target of rapamycin signaling pathway for cancer. Expert Opin Investig Drugs. 2010 Aug;19(8):919-30. doi: 10.1517/13543784.2010.499121. [Article]
- Coppin C: Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Biologics. 2010 May 25;4:91-101. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Everolimus FDA label [File]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- Picard N, Levoir L, Lamoureux F, Yee SW, Giacomini KM, Marquet P: Interaction of sirolimus and everolimus with hepatic and intestinal organic anion-transporting polypeptide transporters. Xenobiotica. 2011 Sep;41(9):752-7. doi: 10.3109/00498254.2011.573882. Epub 2011 Apr 27. [Article]
- Votubia, INN:EVEROLIMUS - European Medicines Agency - europa.eu [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- Picard N, Levoir L, Lamoureux F, Yee SW, Giacomini KM, Marquet P: Interaction of sirolimus and everolimus with hepatic and intestinal organic anion-transporting polypeptide transporters. Xenobiotica. 2011 Sep;41(9):752-7. doi: 10.3109/00498254.2011.573882. Epub 2011 Apr 27. [Article]
- Votubia, INN:EVEROLIMUS - European Medicines Agency - europa.eu [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Na(+)-independent transporter that mediates the cellular uptake of a broad range of organic anions such as the endogenous bile salts cholate and deoxycholate, either in their unconjugated or conjugated forms (taurocholate and glycocholate), at the plasmam membrane (PubMed:19129463, PubMed:7557095). Responsible for intestinal absorption of bile acids (By similarity). Transports dehydroepiandrosterone 3-sulfate (DHEAS), a major circulating steroid secreted by the adrenal cortex, as well as estrone 3-sulfate and 17beta-estradiol 17-O-(beta-D-glucuronate) (PubMed:11159893, PubMed:12568656, PubMed:19129463, PubMed:23918469, PubMed:25560245, PubMed:9539145). Mediates apical uptake of all-trans-retinol (atROL) across human retinal pigment epithelium, which is essential to maintaining the integrity of the visual cycle and thus vision (PubMed:25560245). Involved in the uptake of clinically used drugs (PubMed:17301733, PubMed:20686826, PubMed:27777271). Capable of thyroid hormone transport (both T3 or 3,3',5'-triiodo-L-thyronine, and T4 or L-tyroxine) (PubMed:19129463, PubMed:20358049). Also transports prostaglandin E2 (PubMed:19129463). Plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells (By similarity). May also play a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- bile acid transmembrane transporter activity
- Gene Name
- SLCO1A2
- Uniprot ID
- P46721
- Uniprot Name
- Solute carrier organic anion transporter family member 1A2
- Molecular Weight
- 74144.105 Da
References
- Picard N, Levoir L, Lamoureux F, Yee SW, Giacomini KM, Marquet P: Interaction of sirolimus and everolimus with hepatic and intestinal organic anion-transporting polypeptide transporters. Xenobiotica. 2011 Sep;41(9):752-7. doi: 10.3109/00498254.2011.573882. Epub 2011 Apr 27. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
Drug created at August 29, 2007 15:37 / Updated at October 11, 2024 18:19