Explore a selection of our essential drug information below, or:
Identification
- Summary
Sorafenib is a kinase inhibitor used to treat unresectable liver carcinoma, advanced renal carcinoma, and differentiated thyroid carcinoma.
- Brand Names
- Nexavar
- Generic Name
- Sorafenib
- DrugBank Accession Number
- DB00398
- Background
Sorafenib is a bi-aryl urea and an oral multikinase inhibitor. It targets cell surface tyrosine kinase receptors and downstream intracellular kinases that are implicated in tumour cell proliferation and tumour angiogenesis.1 First approved by the FDA and European Commission in 2007 for the treatment of hepatocellular carcinoma, sorafenib is also indicated to treat renal carcinoma and differentiated thyroid carcinoma.3
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Sorafenib (DB00398)
- Weight
- Average: 464.825
Monoisotopic: 464.08630272 - Chemical Formula
- C21H16ClF3N4O3
- Synonyms
- 4-(4-((((4-Chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide
- N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea
- Sorafenib
- Sorafénib
- Sorafenibum
- External IDs
- BAY 43-9006
- BAY-43-9006
Pharmacology
- Indication
Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.5,6
In the US, it is also indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma that is refractory to radioactive iodine treatment.5
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Advanced renal cell carcinoma (arcc) •••••••••••• •••••• Treatment of Advanced renal cell carcinoma (arcc) •••••••••••• •••••• Treatment of Angiosarcoma ••• ••••• •••••• Treatment of Gastrointestinal stromal tumor ••• ••••• •••••• Treatment of Leiomyosarcoma (lms) ••• ••••• •••••• - Contraindications & Blackbox Warnings
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Sorafenib decreases tumour cell proliferation in vitro. It attenuated tumour growth of human tumour xenografts in immunocompromised mice, reduced tumour angiogenesis, and increased tumour apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma.1,5 Some studies suggest that sorafenib induces apoptosis in several tumour cell lines, although this effect is inconsistent across cell lines.1 Antiviral effects of sorafenib have been documented, as it was shown to inhibit hepatitis C viral replication in vitro.1
- Mechanism of action
Kinases are involved in tumour cell signalling, proliferation, angiogenesis, and apoptosis.3,5 Sorafenib inhibits multiple intracellular serine/threonine kinases in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Intracellular Raf serine/threonine kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-type B-Raf, and mutant B-Raf. Sorafenib inhibits cell surface tyrosine kinase receptors such as KIT, FMS-like tyrosine kinase 3 (FLT-3), RET, RET/PTC, vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor-β (PDGFR-β).1,2,3,5
Sorafenib is thought to exhibit a dual mechanism of action: it blocks tumour proliferation and growth by inhibiting the RAF/MEK/extracellular signal-regulated kinase (ERK) pathway on tumour cells, and reduces tumour angiogenesis by inhibiting VEGFR and PDGFR signalling in tumour vasculature.1,4
Target Actions Organism ASerine/threonine-protein kinase B-raf inhibitorHumans AEpidermal growth factor receptor inhibitorHumans ARAF proto-oncogene serine/threonine-protein kinase inhibitorHumans AVascular endothelial growth factor receptor 3 inhibitorHumans AVascular endothelial growth factor receptor 2 inhibitorHumans AVascular endothelial growth factor receptor 1 inhibitorHumans AReceptor-type tyrosine-protein kinase FLT3 inhibitorHumans APlatelet-derived growth factor receptor beta inhibitorHumans AMast/stem cell growth factor receptor Kit antagonistHumans AFibroblast growth factor receptor 1 inhibitorHumans AProto-oncogene tyrosine-protein kinase receptor Ret inhibitorHumans - Absorption
The administration of multiple doses for seven days resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state concentrations were achieved within seven days, with a peak-to-trough ratio of mean concentrations of less than 2. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. The Tmax is approximately three hours.5
The mean relative bioavailability was 38–49% following the administration of oral sorafenib tablets. A high-fat meal reduced bioavailability by 29%.5
- Volume of distribution
Sorafenib is widely distributed to tissues, indicating that it is lipophilic.1
- Protein binding
In vitro, sorafenib is 99.5% bound to human plasma proteins.5
- Metabolism
Sorafenib undergoes oxidative metabolism by CYP3A4 in the liver, as well as glucuronidation by UGT1A9 in the liver and kidneys.1,5 At steady-state, sorafenib accounts for 70-85% of the circulating analytes in plasma.1 About eight metabolites of sorafenib have been identified, of which five were detected in plasma. The main circulating metabolite was the pyridine N-oxide form, which comprises approximately 9–16% of the total circulating dose at steady-state: the pharmacological activity of this metabolite was comparable to the parent drug.5
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- Route of elimination
Following oral administration of a 100 mg dose of sorafenib, about 96% of the dose was recovered within 14 days, with 77% of the dose being excreted in feces and 19% of the dose being excreted in urine as glucuronidated metabolites. Unchanged sorafenib accounted for 51% of the dose excreted in feces.5
- Half-life
The mean elimination half-life of sorafenib was approximately 25 to 48 hours.5
- Clearance
Not Available
- Adverse Effects
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The oral lowest published toxic dose (Toxic Dose Low, TDLo) is 2.84 mg/kg/21D (intermittent).7 The oral LD50 of sorafenib tosylate in rats is >2000 mg/kg.8
The adverse reactions observed at 800 mg sorafenib twice daily (twice the recommended dose) were primarily diarrhea and dermatologic. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals. The prescribing information recommends the discontinuation of sorafenib treatment and initiation of supportive care in cases of suspected overdose.5
- Pathways
Pathway Category Sorafenib Metabolism Pathway Drug metabolism - 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 softwareAbacavir The metabolism of Abacavir can be decreased when combined with Sorafenib. Abametapir The serum concentration of Sorafenib can be increased when it is combined with Abametapir. Abatacept The metabolism of Sorafenib can be increased when combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Sorafenib. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Sorafenib. - Food Interactions
- Do not take with or immediately after a high-fat meal. Take sorafenib at least 1 hour before or 2 hours after a high-fat meal, as sorafenib absorption can be reduced by a high-fat meal.
- Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of sorafenib.
- Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of sorafenib.
- Take on an empty stomach. Take sorafenib at least one hour before or two hours after a meal.
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.- Product Ingredients
Ingredient UNII CAS InChI Key Sorafenib tosylate 5T62Q3B36J 475207-59-1 IVDHYUQIDRJSTI-UHFFFAOYSA-N - Product Images
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Nexavar Tablet, film coated 200 mg Oral Bayer Ag 2016-09-08 Not applicable EU 
Nexavar Tablet, film coated 200 mg/1 Oral Bayer HealthCare Pharmaceuticals Inc. 2005-12-20 Not applicable US 
Nexavar Tablet, film coated 200 mg/1 Oral Bayer HealthCare Pharmaceuticals Inc. 2023-10-02 Not applicable US Nexavar Tablet, film coated 200 mg/1 Oral Bayer Pharmaceuticals Corporartion 2007-02-23 2007-02-23 US Nexavar Tablet 200 mg Oral Bayer Ag 2006-07-31 Not applicable Canada 
- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Apo-sorafenib Tablet 200 mg Oral Apotex Corporation Not applicable Not applicable Canada Sorafenib Tablet, film coated 200 mg/1 Oral Torrent Pharmaceuticals Limited 2023-04-12 Not applicable US Sorafenib Tablet, film coated 200 mg/1 Oral TWi Pharmaceuticals USA, Inc. 2022-12-01 Not applicable US Sorafenib Tablet, film coated 200 mg/1 Oral Dr. Reddy's Laboratories Limited 2022-06-08 Not applicable US Sorafenib Tablet, film coated 200 mg/1 Oral Bora Pharmaceutical Laboratories Inc. 2022-12-01 Not applicable US
Categories
- ATC Codes
- L01EX02 — Sorafenib
- Drug Categories
- Amides
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- Benzene Derivatives
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP1A2 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2B6 Inhibitors
- Cytochrome P-450 CYP2B6 Inhibitors (moderate)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C8 Inhibitors (strong)
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C8 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strong)
- 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 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 CYP3A5 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A7 Substrates
- Cytochrome P-450 CYP3A7 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Drugs that are Mainly Renally Excreted
- Enzyme Inhibitors
- Immunosuppressive Agents
- Kinase Inhibitor
- Myelosuppressive Agents
- Narrow Therapeutic Index Drugs
- Nicotinic Acids
- OATP1B1/SLCO1B1 Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Phenylurea Compounds
- Potential QTc-Prolonging Agents
- Protein Kinase Inhibitors
- Pyridines
- QTc Prolonging Agents
- Tyrosine Kinase Inhibitors
- UGT1A1 Inhibitors
- UGT1A9 Inhibitors
- UGT1A9 Substrates
- UGT1A9 Substrates with a Narrow Therapeutic Index
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
- Kingdom
- Organic compounds
- Super Class
- Organic oxygen compounds
- Class
- Organooxygen compounds
- Sub Class
- Ethers
- Direct Parent
- Diarylethers
- Alternative Parents
- Trifluoromethylbenzenes / N-phenylureas / Pyridinecarboxamides / 2-heteroaryl carboxamides / Phenoxy compounds / Phenol ethers / Chlorobenzenes / Aryl chlorides / Heteroaromatic compounds / Secondary carboxylic acid amides show 10 more
- Substituents
- 2-heteroaryl carboxamide / Alkyl fluoride / Alkyl halide / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonic acid derivative / Carbonyl group show 25 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- aromatic ether, ureas, monochlorobenzenes, (trifluoromethyl)benzenes, pyridinecarboxamide (CHEBI:50924)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 9ZOQ3TZI87
- CAS number
- 284461-73-0
- InChI Key
- MLDQJTXFUGDVEO-UHFFFAOYSA-N
- InChI
- InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
- IUPAC Name
- 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide
- SMILES
- CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1
References
- Synthesis Reference
Ales Gavenda, Alexandr Jegorov, Pierluigi Rossetto, Peter Lindsay MacDonald, Augusto Canavesi, "POLYMORPHS OF SORAFENIB TOSYLATE AND SORAFENIB HEMI-TOSYLATE, AND PROCESSES FOR PREPARATION THEREOF." U.S. Patent US20090192200, issued July 30, 2009.
US20090192200- General References
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Keating GM: Sorafenib: A Review in Hepatocellular Carcinoma. Target Oncol. 2017 Apr;12(2):243-253. doi: 10.1007/s11523-017-0484-7. [Article]
- Keating GM, Santoro A: Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009;69(2):223-40. doi: 10.2165/00003495-200969020-00006. [Article]
- Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. [Article]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- EMA Approved Drug Products: Sorafenib Accord Oral Tablets [Link]
- Cayman Chemical: Sorafenib MSDS [Link]
- CymitQuimica: Sorafenib Tosylate MSDS [Link]
- External Links
- Human Metabolome Database
- HMDB0014542
- KEGG Drug
- D08524
- PubChem Compound
- 216239
- PubChem Substance
- 46505329
- ChemSpider
- 187440
- BindingDB
- 16673
- 495881
- ChEBI
- 50924
- ChEMBL
- CHEMBL1336
- ZINC
- ZINC000001493878
- Therapeutic Targets Database
- DAP000006
- PharmGKB
- PA7000
- PDBe Ligand
- BAX
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Sorafenib
- PDB Entries
- 1uwh / 1uwj / 3gcs / 3heg / 3rgf / 3wze / 4asd / 5hi2
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 Active Not Recruiting Not Available Hepatocellular Carcinoma / Microvascular Invasion (MVI) / Multi-kinase Inhibitors (MKI) / Radiomics / Transcatheter Arterial Chemoembolization (TACE) 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Not Available Thyroid Carcinoma 1 somestatus stop reason just information to hide Not Available Available Not Available Gastric Cancer 1 somestatus stop reason just information to hide Not Available Completed Not Available Acute Myeloid Leukemia / Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) / Internal Tandem Duplication (ITD) Mutation / Hematopoietic Stem Cell Transplantation (SCT) 1 somestatus stop reason just information to hide Not Available Completed Not Available Advanced Renal Cell Carcinoma / Renal Cell Carcinoma (RCC) 2 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Bayer healthcare pharmaceuticals inc
- Packagers
- Bayer Healthcare
- Dosage Forms
Form Route Strength Tablet Oral 200 mg Tablet, coated Oral 200 mg Tablet, film coated Oral 200 mg/1 Tablet, film coated Oral 274 mg Tablet, film coated Oral 400 mg Tablet, film coated Oral Tablet, film coated Oral 200 MG Tablet Oral 274.570 mg - Prices
Unit description Cost Unit Nexavar 200 mg tablet 66.61USD 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 CA2315715 No 2010-06-22 2018-12-22 Canada CA2359510 No 2007-02-13 2020-01-12 Canada US8618141 No 2013-12-31 2023-02-11 US US8877933 No 2014-11-04 2027-12-24 US US8124630 No 2012-02-28 2020-01-12 US US8841330 No 2014-09-23 2020-01-12 US US7235576 No 2007-06-26 2020-01-12 US US7897623 No 2011-03-01 2020-01-12 US US7351834 No 2008-04-01 2020-01-12 US US9737488 No 2017-08-22 2028-09-10 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 187-226 https://static.cymitquimica.com/products/45/pdf/sds-1615876.pdf water solubility < 0.01 g/L https://static.cymitquimica.com/products/45/pdf/sds-1615876.pdf - Predicted Properties
Property Value Source Water Solubility 0.00171 mg/mL ALOGPS logP 4.12 ALOGPS logP 4.34 Chemaxon logS -5.4 ALOGPS pKa (Strongest Acidic) 11.55 Chemaxon pKa (Strongest Basic) 3.03 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 92.35 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 114.52 m3·mol-1 Chemaxon Polarizability 41.33 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9649 Blood Brain Barrier + 0.851 Caco-2 permeable - 0.5138 P-glycoprotein substrate Non-substrate 0.5086 P-glycoprotein inhibitor I Non-inhibitor 0.7141 P-glycoprotein inhibitor II Non-inhibitor 0.9359 Renal organic cation transporter Non-inhibitor 0.8938 CYP450 2C9 substrate Non-substrate 0.6569 CYP450 2D6 substrate Non-substrate 0.8212 CYP450 3A4 substrate Non-substrate 0.5341 CYP450 1A2 substrate Inhibitor 0.6168 CYP450 2C9 inhibitor Non-inhibitor 0.6171 CYP450 2D6 inhibitor Non-inhibitor 0.9145 CYP450 2C19 inhibitor Inhibitor 0.637 CYP450 3A4 inhibitor Non-inhibitor 0.7339 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6629 Ames test Non AMES toxic 0.8143 Carcinogenicity Non-carcinogens 0.8684 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.7885 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9488 hERG inhibition (predictor II) Non-inhibitor 0.6415
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-022j-2972400000-d028d5e696594206a526 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0159-0010900000-745ff5021ea7edf6a854 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0159-0010900000-fd12a6fffe62eb724145 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0007-0902400000-47964cccaeafdb854d16 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-01p9-1693400000-3024d29de7aea58e8889 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-000f-3940100000-1267858fe6e7286d568b Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-6915200000-fce06bd0ce7d2573ff8f Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 222.7914665 predictedDarkChem Lite v0.1.0 [M-H]- 201.7416 predictedDeepCCS 1.0 (2019) [M+H]+ 224.0945665 predictedDarkChem Lite v0.1.0 [M+H]+ 204.13716 predictedDeepCCS 1.0 (2019) [M+Na]+ 222.9889665 predictedDarkChem Lite v0.1.0 [M+Na]+ 210.0703 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- It binds to Ras/Raf with an IC50 40 ng/mL.
- General Function
- Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role in the postsynaptic responses of hippocampal neurons (PubMed:1508179)
- Specific Function
- ATP binding
- Gene Name
- BRAF
- Uniprot ID
- P15056
- Uniprot Name
- Serine/threonine-protein kinase B-raf
- Molecular Weight
- 84436.135 Da
References
- Flaherty KT: Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2366s-2370s. [Article]
- Haluska FG, Ibrahim N: Therapeutic targets in melanoma: map kinase pathway. Curr Oncol Rep. 2006 Sep;8(5):400-5. [Article]
- Kim S, Yazici YD, Calzada G, Wang ZY, Younes MN, Jasser SA, El-Naggar AK, Myers JN: Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther. 2007 Jun;6(6):1785-92. [Article]
- Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, Marais R, Gibbens I, Hackett S, James M, Schuchter LM, Nathanson KL, Xia C, Simantov R, Schwartz B, Poulin-Costello M, O'Dwyer PJ, Ratain MJ: Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer. 2006 Sep 4;95(5):581-6. Epub 2006 Aug 1. [Article]
- Lu X, Tang X, Guo W, Ren T, Zhao H: Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway. J Surg Oncol. 2010 Dec 1;102(7):821-6. doi: 10.1002/jso.21661. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:10805725, PubMed:27153536, PubMed:2790960, PubMed:35538033). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:12297049, PubMed:15611079, PubMed:17909029, PubMed:20837704, PubMed:27153536, PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity)
- Specific Function
- actin filament binding
- Gene Name
- EGFR
- Uniprot ID
- P00533
- Uniprot Name
- Epidermal growth factor receptor
- Molecular Weight
- 134276.185 Da
References
- 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]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation
- Specific Function
- ATP binding
- Gene Name
- RAF1
- Uniprot ID
- P04049
- Uniprot Name
- RAF proto-oncogene serine/threonine-protein kinase
- Molecular Weight
- 73051.025 Da
References
- Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. [Article]
- Gollob JA, Wilhelm S, Carter C, Kelley SL: Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol. 2006 Aug;33(4):392-406. [Article]
- Huether A, Hopfner M, Baradari V, Schuppan D, Scherubl H: Sorafenib alone or as combination therapy for growth control of cholangiocarcinoma. Biochem Pharmacol. 2007 May 1;73(9):1308-17. Epub 2007 Jan 5. [Article]
- Cascone T, Gridelli C, Ciardiello F: Combined targeted therapies in non-small cell lung cancer: a winner strategy? Curr Opin Oncol. 2007 Mar;19(2):98-102. [Article]
- Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A: Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007 Feb;12(2):191-200. [Article]
- Lu X, Tang X, Guo W, Ren T, Zhao H: Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway. J Surg Oncol. 2010 Dec 1;102(7):821-6. doi: 10.1002/jso.21661. [Article]
- Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M: CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009 Jan 8;28(1):85-94. doi: 10.1038/onc.2008.362. Epub 2008 Sep 15. [Article]
- Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M: Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008 Oct;7(10):3129-40. doi: 10.1158/1535-7163.MCT-08-0013. [Article]
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'
- Specific Function
- ATP binding
- Gene Name
- FLT4
- Uniprot ID
- P35916
- Uniprot Name
- Vascular endothelial growth factor receptor 3
- Molecular Weight
- 152755.94 Da
References
- Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P: Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol. 2006 May;57(5):685-92. Epub 2005 Aug 25. [Article]
- Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. [Article]
- Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A: Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist. 2007 Feb;12(2):191-200. [Article]
- Strumberg D: Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc). 2005 Dec;41(12):773-84. [Article]
- Reddy GK, Bukowski RM: Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma. Clin Genitourin Cancer. 2006 Mar;4(4):246-8. [Article]
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- It binds to VEGFR-2 with an IC50 of 570 ng/mL.
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC
- Specific Function
- ATP binding
- Gene Name
- KDR
- Uniprot ID
- P35968
- Uniprot Name
- Vascular endothelial growth factor receptor 2
- Molecular Weight
- 151525.555 Da
References
- Schoffski P, Dumez H, Clement P, Hoeben A, Prenen H, Wolter P, Joniau S, Roskams T, Van Poppel H: Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol. 2006 Aug;17(8):1185-96. Epub 2006 Jan 17. [Article]
- Veronese ML, Mosenkis A, Flaherty KT, Gallagher M, Stevenson JP, Townsend RR, O'Dwyer PJ: Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006 Mar 20;24(9):1363-9. Epub 2006 Jan 30. [Article]
- Rini BI: Sorafenib. Expert Opin Pharmacother. 2006 Mar;7(4):453-61. [Article]
- Adnane L, Trail PA, Taylor I, Wilhelm SM: Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 2006;407:597-612. [Article]
- Lacouture ME, Desai A, Soltani K, Petronic-Rosic V, Laumann AE, Ratain MJ, Stadler WM: Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin Exp Dermatol. 2006 Nov;31(6):783-5. Epub 2006 Jul 4. [Article]
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- It binds to VEGFR-1 with an IC50 of 165 ng/mL.
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. Acts as a positive regulator of postnatal retinal hyaloid vessel regression (By similarity). May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1 (PubMed:16685275)
- Specific Function
- ATP binding
- Gene Name
- FLT1
- Uniprot ID
- P17948
- Uniprot Name
- Vascular endothelial growth factor receptor 1
- Molecular Weight
- 150767.185 Da
References
- Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [Article]
- Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [Article]
- Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [Article]
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways
- Specific Function
- ATP binding
- Gene Name
- FLT3
- Uniprot ID
- P36888
- Uniprot Name
- Receptor-type tyrosine-protein kinase FLT3
- Molecular Weight
- 112902.51 Da
References
- Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y, Zhang X, Wilkie D, Burd A, Shi H, Rocks S, Gedrich R, Abriola L, Vasavada H, Lynch M, Dumas J, Trail PA, Wilhelm SM: Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia. 2007 Mar;21(3):439-45. Epub 2007 Jan 4. [Article]
- Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J: The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007 Jan;92(1):27-34. [Article]
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor
- Specific Function
- ATP binding
- Gene Name
- PDGFRB
- Uniprot ID
- P09619
- Uniprot Name
- Platelet-derived growth factor receptor beta
- Molecular Weight
- 123966.895 Da
References
- Gollob JA: Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer. 2005 Dec;4(3):167-74. [Article]
- Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, Carlomagno F: Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res. 2007 Jun 1;13(11):3363-9. [Article]
- Unnithan J, Rini BI: The role of targeted therapy in metastatic renal cell carcinoma. ScientificWorldJournal. 2007 Mar 2;7:800-7. [Article]
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1
- Specific Function
- ATP binding
- Gene Name
- KIT
- Uniprot ID
- P10721
- Uniprot Name
- Mast/stem cell growth factor receptor Kit
- Molecular Weight
- 109863.655 Da
References
- Guida T, Anaganti S, Provitera L, Gedrich R, Sullivan E, Wilhelm SM, Santoro M, Carlomagno F: Sorafenib inhibits imatinib-resistant KIT and platelet-derived growth factor receptor beta gatekeeper mutants. Clin Cancer Res. 2007 Jun 1;13(11):3363-9. [Article]
- Koch CA, Gimm O, Vortmeyer AO, Al-Ali HK, Lamesch P, Ott R, Kluge R, Bierbach U, Tannapfel A: Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy? Ann N Y Acad Sci. 2006 Aug;1073:517-26. [Article]
- Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J: The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica. 2007 Jan;92(1):27-34. [Article]
- Cascone T, Gridelli C, Ciardiello F: Combined targeted therapies in non-small cell lung cancer: a winner strategy? Curr Opin Oncol. 2007 Mar;19(2):98-102. [Article]
- Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006 Dec 15;66(24):11851-8. [Article]
- Iyer R, Fetterly G, Lugade A, Thanavala Y: Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010 Aug;11(11):1943-55. doi: 10.1517/14656566.2010.496453. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation
- Specific Function
- ATP binding
- Gene Name
- FGFR1
- Uniprot ID
- P11362
- Uniprot Name
- Fibroblast growth factor receptor 1
- Molecular Weight
- 91866.935 Da
References
- Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [Article]
- Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [Article]
- Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15) (PubMed:20064382, PubMed:20616503, PubMed:20702524, PubMed:21357690, PubMed:21454698, PubMed:24560924, PubMed:28846097, PubMed:28846099, PubMed:28953886, PubMed:31118272). In contrast to most receptor tyrosine kinases, RET requires not only its cognate ligands but also coreceptors, for activation (PubMed:21994944, PubMed:23333276, PubMed:28846097, PubMed:28846099, PubMed:28953886). GDNF ligands (GDNF, NRTN, ARTN, PSPN and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways (PubMed:21994944, PubMed:23333276, PubMed:24560924, PubMed:25242331, PubMed:28846097, PubMed:28846099, PubMed:28953886). Acts as a dependence receptor via the GDNF-GFRA1 signaling: in the presence of the ligand GDNF in somatotrophs within pituitary, promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF (PubMed:20616503, PubMed:21994944). Required for the molecular mechanisms orchestration during intestine organogenesis via the ARTN-GFRA3 signaling: involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue (By similarity). Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses (PubMed:28846097, PubMed:28846099, PubMed:28953886). Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner (PubMed:20702524, PubMed:21357690). Also active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage (PubMed:21357690). Triggers the differentiation of rapidly adapting (RA) mechanoreceptors (PubMed:20064382). Involved in the development of the neural crest (By similarity). Regulates nociceptor survival and size (By similarity). Phosphorylates PTK2/FAK1 (PubMed:21454698)
- Specific Function
- ATP binding
- Gene Name
- RET
- Uniprot ID
- P07949
- Uniprot Name
- Proto-oncogene tyrosine-protein kinase receptor Ret
- Molecular Weight
- 124317.465 Da
References
- Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004 Oct 1;64(19):7099-109. [Article]
- Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, Santoro M: BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006 Mar 1;98(5):326-34. [Article]
- Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S: Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006 Oct;5(10):835-44. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- Curator comments
- Sorafenib competitively inhibited CYP3A4 in vitro.
- 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
- Gomo C, Coriat R, Faivre L, Mir O, Ropert S, Billemont B, Dauphin A, Tod M, Goldwasser F, Blanchet B: Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011 Dec;29(6):1511-4. doi: 10.1007/s10637-010-9514-3. Epub 2010 Aug 13. [Article]
- van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [Article]
- Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
- Sugiyama M, Fujita K, Murayama N, Akiyama Y, Yamazaki H, Sasaki Y: Sorafenib and sunitinib, two anticancer drugs, inhibit CYP3A4-mediated and activate CY3A5-mediated midazolam 1'-hydroxylation. Drug Metab Dispos. 2011 May;39(5):757-62. doi: 10.1124/dmd.110.037853. Epub 2011 Jan 25. [Article]
- Flockhart Table of Drug Interactions [Link]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Sorafenib competitively inhibited CYP2C9 in vitro.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). 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:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Gong L, Giacomini MM, Giacomini C, Maitland ML, Altman RB, Klein TE: PharmGKB summary: sorafenib pathways. Pharmacogenet Genomics. 2017 Jun;27(6):240-246. doi: 10.1097/FPC.0000000000000279. [Article]
- Holstein A, Kovacs P, Beil W: Severe hypoglycemia due to possible interaction between glibenclamide and sorafenib in a patient with hepatocellular carcinoma. Curr Drug Saf. 2013 Apr;8(2):148-52. [Article]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- Curator comments
- Sorafenib competitively inhibited CYP2C8 in vitro.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). 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:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
- Flockhart Table of Drug Interactions [Link]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). 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:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion 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 all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
- Specific Function
- aromatase activity
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Flockhart Table of Drug Interactions [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins during embryogenesis (PubMed:11093772, PubMed:12865317, PubMed:14559847, PubMed:17178770, PubMed:9555064). 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:11093772, PubMed:12865317, PubMed:14559847, PubMed:17178770, PubMed:9555064). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone, DHEA), a precursor in the biosynthesis of androgen and estrogen steroid hormones (PubMed:17178770, PubMed:9555064). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1), particularly D-ring hydroxylated estrone at the C16-alpha position (PubMed:12865317, PubMed:14559847). Mainly hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in atRA clearance during fetal development (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics including anticonvulsants (PubMed:9555064)
- Specific Function
- all-trans retinoic acid 18-hydroxylase activity
- Gene Name
- CYP3A7
- Uniprot ID
- P24462
- Uniprot Name
- Cytochrome P450 3A7
- Molecular Weight
- 57469.95 Da
References
- Flockhart Table of Drug Interactions [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Sorafenib competitively inhibited CYP2B6 in vitro.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). 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 epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
- Flockhart Table of Drug Interactions [Link]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). 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:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
- Zimmerman EI, Roberts JL, Li L, Finkelstein D, Gibson A, Chaudhry AS, Schuetz EG, Rubnitz JE, Inaba H, Baker SD: Ontogeny and sorafenib metabolism. Clin Cancer Res. 2012 Oct 15;18(20):5788-95. doi: 10.1158/1078-0432.CCR-12-1967. Epub 2012 Aug 27. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Sorafenib competitively inhibited CYP2C19 in vitro.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). 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:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Sorafenib competitively inhibited CYP2D6 in vitro.
- 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
References
- Flaherty KT, Lathia C, Frye RF, Schuchter L, Redlinger M, Rosen M, O'Dwyer PJ: Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8. doi: 10.1007/s00280-011-1585-0. Epub 2011 Feb 25. [Article]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15470161, PubMed:15472229, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:19545173). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:20610558). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A9
- Uniprot ID
- O60656
- Uniprot Name
- UDP-glucuronosyltransferase 1A9
- Molecular Weight
- 59940.495 Da
References
- Gomo C, Coriat R, Faivre L, Mir O, Ropert S, Billemont B, Dauphin A, Tod M, Goldwasser F, Blanchet B: Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011 Dec;29(6):1511-4. doi: 10.1007/s10637-010-9514-3. Epub 2010 Aug 13. [Article]
- van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. doi: 10.1016/j.ctrv.2009.08.004. Epub 2009 Sep 5. [Article]
- Keating GM, Santoro A: Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs. 2009;69(2):223-40. doi: 10.2165/00003495-200969020-00006. [Article]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1A1
- Molecular Weight
- 59590.91 Da
References
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
Transporters
- 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
References
- Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [Article]
- Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH: Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther. 2010 Feb;9(2):319-26. doi: 10.1158/1535-7163.MCT-09-0663. Epub 2010 Jan 26. [Article]
- FDA Approved Drug Products: NEXAVAR (sorafenib) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- Curator comments
- The literature seems to reflect that Sorafenib is either strictly a substrate or an inhibitor.
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [Article]
- Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH: Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther. 2010 Feb;9(2):319-26. doi: 10.1158/1535-7163.MCT-09-0663. Epub 2010 Jan 26. [Article]
- Wei Y, Ma Y, Zhao Q, Ren Z, Li Y, Hou T, Peng H: New use for an old drug: inhibiting ABCG2 with sorafenib. Mol Cancer Ther. 2012 Aug;11(8):1693-702. doi: 10.1158/1535-7163.MCT-12-0215. Epub 2012 May 16. [Article]
- Huang WC, Hsieh YL, Hung CM, Chien PH, Chien YF, Chen LC, Tu CY, Chen CH, Hsu SC, Lin YM, Chen YJ: BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib. PLoS One. 2013 Dec 31;8(12):e83627. doi: 10.1371/journal.pone.0083627. eCollection 2013. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12523936, PubMed:12835412, PubMed:12883481, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12523936, PubMed:12883481, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:17344354, PubMed:18300232). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685)
- Specific Function
- 15-hydroxyprostaglandin dehydrogenase (NAD+) activity
- Gene Name
- ABCC4
- Uniprot ID
- O15439
- Uniprot Name
- ATP-binding cassette sub-family C member 4
- Molecular Weight
- 149525.33 Da
References
- Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:11500505). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:16332456). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (PubMed:10220572, PubMed:11500505, PubMed:12441801). Confers resistance to several anti-cancer drugs including cisplatin, doxorubicin, epirubicin, methotrexate, etoposide and vincristine (PubMed:10220572, PubMed:11500505)
- Specific Function
- ABC-type glutathione S-conjugate transporter activity
- Gene Name
- ABCC2
- Uniprot ID
- Q92887
- Uniprot Name
- ATP-binding cassette sub-family C member 2
- Molecular Weight
- 174205.64 Da
References
- Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD: Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res. 2009 Oct 1;15(19):6062-9. doi: 10.1158/1078-0432.CCR-09-0048. Epub 2009 Sep 22. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Multifunctional protein that functions as a downstream effector of RALA and RALB (PubMed:7673236). As a GTPase-activating protein/GAP can inactivate CDC42 and RAC1 by stimulating their GTPase activity (PubMed:7673236). As part of the Ral signaling pathway, may also regulate ligand-dependent EGF and insulin receptors-mediated endocytosis (PubMed:10910768, PubMed:12775724). During mitosis, may act as a scaffold protein in the phosphorylation of EPSIN/EPN1 by the mitotic kinase cyclin B-CDK1, preventing endocytosis during that phase of the cell cycle (PubMed:12775724). During mitosis, also controls mitochondrial fission as an effector of RALA (PubMed:21822277). Recruited to mitochondrion by RALA, acts as a scaffold to foster the mitotic kinase cyclin B-CDK1-mediated phosphorylation and activation of DNM1L (PubMed:21822277)
- Specific Function
- ABC-type glutathione S-conjugate transporter activity
- Gene Name
- RALBP1
- Uniprot ID
- Q15311
- Uniprot Name
- RalA-binding protein 1
- Molecular Weight
- 76062.86 Da
References
- Singhal SS, Sehrawat A, Sahu M, Singhal P, Vatsyayan R, Rao Lelsani PC, Yadav S, Awasthi S: Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 2010 Mar 15;126(6):1327-38. doi: 10.1002/ijc.24767. [Article]
- 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
- Hu S, Mathijssen RH, de Bruijn P, Baker SD, Sparreboom A: Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations. Br J Cancer. 2014 Feb 18;110(4):894-8. doi: 10.1038/bjc.2013.811. Epub 2014 Jan 7. [Article]
Drug created at June 13, 2005 13:24 / Updated at October 21, 2024 12:34