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Identification
- Summary
Selumetinib is a MEK 1/2 inhibitor used in pediatric patients to treat neurofibromatosis type 1 (NF1) accompanied by symptomatic, inoperable plexiform neurofibromas (PN).
- Brand Names
- Koselugo
- Generic Name
- Selumetinib
- DrugBank Accession Number
- DB11689
- Background
Activation of the Raf-MEK-ERK signalling pathway is known to be implemented in several types of malignancies; thus, mitogen-activated protein kinase kinase (MEK) inhibitors such as selumetinib are important tools that can target the problematic overactivity of this pathway.6 Results from clinical trials investigating earlier developed MEK inhibitors were underwhelming.6 However, selumetinib demonstrated impressive efficacy and tolerability in Phase I trials, leading to its continued investigation for the treatment of various types of tumours in Phase II trials.6
Currently, the novel MEK 1 / 2 inhibitor, selumetinib, is approved solely for the treatment of Neurofibromatosis type 1 (NF-1) in a limited age group. NF-1 is considered rare, with an estimated incidence of 1/3000 individuals.5 It is a genetic, autosomal dominant condition resulting from mutations of the NF1 gene, which can lead to various complications, including the development of multiple tumours in the nervous system.3,5 Some patients with this disorder develop plexiform neurofibromas (PN); however, this is considered relatively uncommon compared to other variants of NF-1.5 Luckily, the use of selumetinib in patients with NF-1 have shown efficacy in shrinking associated tumours and is linked to other positive clinical outcomes.3 Selumetinib was approved by the FDA on April 10, 2020.16 It was later approved by Health Canada on August 23, 2022.15
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Selumetinib (DB11689)
- Weight
- Average: 457.68
Monoisotopic: 456.000009 - Chemical Formula
- C17H15BrClFN4O3
- Synonyms
- Selumetinib
- Sélumétinib
- Selumetinibum
- External IDs
- ARRY 142886
- ARRY-142886
- ARRY142886
- AZD 6244
- AZD-6244
- AZD6244
Pharmacology
- Indication
Selumetinib is indicated for the treatment of neurofibromatosis type 1 (NF1) in patients two years and older who have symptomatic, inoperable plexiform neurofibromas (PN).6,13,14,15
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Neurofibromatosis type 1 (nf1) •••••••••••• ••••••••• •••••••••••• •••••••••• ••••••••• ••••••••••••• ••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Selumetinib is a non-ATP-competitive mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) inhibitor.6 By selectively targeting MEK1 and MEK2, selumetinib is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often overactive in certain types of cancer.6 Indeed, a study investigating the effects of selumetinib in children with NF-1 found that treatment with the anti-neoplastic resulted in reduced tumor size.3 Decreases in tumor-associated pain and improvements in overall function were also subjectively reported.3
Selumetinib has minimal off-target activity, contributing to its impressive safety profile.11
- Mechanism of action
The Ras-Raf-MEK-ERK signaling cascade is known to be activated in several types of cancer, and regulates the transcription of proteins involved in apoptosis.7,10 In addition, studies have shown that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance.7,8
Ras as well as several kinases and phosphatases are responsible for regulating the Raf-MEK-ERK pathway.7 Often in cancers, Ras (a G-protein coupled receptor) is deregulated, allowing downstream signalling to proceed unchecked.7 Through several complex steps, Raf phosphorylates and activates MEK, which then phosphorylates and activates ERK.4,7 ERK is then able to exert its effects on several downstream targets.4,7
As such, therapies inhibiting upstream components of this pathway have become attractive targets for cancer treatment.4 Selumetinib exerts its effects by selectively inhibiting MEK1 and MEK2 which can effectively blunt the pleiotropic effects of the Ras-Raf-MEK-ERK cascade.3,9 By inhibiting this oncogenic pathway, selumetinib reduces cell proliferation, and promotes pro-apoptotic signal transduction.4,4,10
Target Actions Organism ADual specificity mitogen-activated protein kinase kinase 1 inhibitorHumans ADual specificity mitogen-activated protein kinase kinase 2 inhibitorHumans - Absorption
Based on several studies investigating selumetinib at various doses in both pediatric and adult populations, the Tmax generally ranges between 1- 1.5 hours.1,2,13 In healthy adults, the mean absolute oral bioavailability was reported to be 62%.13 Selumetinib should be administered on an empty stomach since food significantly decreases serum concentrations of the drug.13
- Volume of distribution
The mean apparent volume of distribution of selumetinib at steady state in pediatric patients ranged from 78 L to 171 L.13
A study in healthy adult males found a mean apparent volume of distribution of 146 L.2
Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found that the apparent volume of distribution values at steady-state ranged from 73.2 - 148.1 L.1
- Protein binding
Separate studies investigating selumetinib protein binding found that 96% of selumetinib was bound to serum albumin, while <35% was bound to ɑ-1 acid glycoprotein.13 Overall, approximately 98.4% of selumetinib is plasma protein bound.13
- Metabolism
Selumetinib is heavily metabolized in the liver and the proposed metabolic pathway is as follows 2:
Hydrolysis of selumetinib’s amide functional group produces M15 (AZ13326637), which contains a carboxylic acid.2
Elimination of the ethanediol moiety from the parent compound results in the formation of the primary amide M14 (AZ12791138) metabolite.2 Amide hydrolysis transforms M14 into M15, glucuronidation and further oxidation of M14 leads to M2, M6 and M1, and N-demethylation of M14 produces M12.2
The amide glucuronide (M2) is thought to be the major circulating metabolite.2
Demethylation of selumetinib produces the pharmacologically active M8 (AZ12442942), and further oxidation of M8 leads to M11.2 Glucuronidation of M8 produces M3 or M5, and elimination of the ethanediol moiety from M8 results in a primary amide, producing M12.2
Although the N-demethylated metabolite (M8) accounts for <10% of the circulating metabolites, it is responsible for approximately 21-35% of any observed pharmacological activity.2,13
Ribose conjugation transforms M12 into M9, while oxidation of M12 leads to M10 and M13 metabolites.2 Glucuronidation of M10 produces M1.2
Direct glucuronidation of selumetinib produces M4 or M7, which can both eventually transform into M3 and M5 metabolites.2
Hover over products below to view reaction partners
- Route of elimination
Approximately 59% of selumetinib is eliminated in the feces, while 33% is eliminated in the urine.2,13
- Half-life
Selumetinib is characterized by a short half-life.1 The elimination half-life associated with a dose of 25 mg/m2 in pediatric patients is 6.2 hours.13
In a study observing the pharmacokinetic effects of various selumetinib regimens in select Japanese patients, the half-life ranged from 9.2- 10.6 hours.1
In other studies where selumetinib 75 mg is administered twice daily, the half-life is reported to be approximately 13 hours.2
- Clearance
The clearance of selumetinib in pediatric patients is 8.8 L/hr.13 A study in healthy adult males found a clearance value of 15.7 L/hr.2 Another study observing the pharmacokinetic effects of various selumetinib doses and regimens in select Japanese patients found clearance values that ranged from 9.2 - 15.9 L/hr.1
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Toxicity information regarding selumetinib is not readily available. Patients experiencing an overdose are at an increased risk of adverse effects such as cardiomyopathy, ocular toxicity, and diarrhea. It is generally thought that since selumetinib is extensively protein-bound, dialysis is unlikely to be helpful in situations of overdose.12,13
- 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 Selumetinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Selumetinib can be increased when combined with Abatacept. Abemaciclib Abemaciclib may decrease the excretion rate of Selumetinib which could result in a higher serum level. Abiraterone The serum concentration of Selumetinib can be increased when it is combined with Abiraterone. Abrocitinib The serum concentration of Selumetinib can be increased when it is combined with Abrocitinib. - Food Interactions
- Take on an empty stomach. Avoid consuming food 2 hours before and 1 hour after each dose.
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 Selumetinib sulfate 807ME4B7IJ 943332-08-9 GRKFGZYYYYISDX-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Koselugo Capsule 25 mg Oral Astra Zeneca Ab 2021-10-25 Not applicable EU 
Koselugo Capsule 25 mg/1 Oral AstraZeneca Pharmaceuticals LP 2020-04-16 Not applicable US 
Koselugo Capsule 10 mg Oral Astra Zeneca Ab 2021-10-25 Not applicable EU Koselugo Capsule 10 mg/1 Oral AstraZeneca Pharmaceuticals LP 2020-04-16 Not applicable US Koselugo Capsule 10 mg Oral Alexion Pharma Gmbh 2023-01-03 Not applicable Canada 
Categories
- ATC Codes
- L01EE04 — Selumetinib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Substrates
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2E1 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Kinase Inhibitor
- Mitogen-activated protein kinase (MEK) inhibitors
- Mitogen-Activated Protein Kinase Kinase 1 Inhibitors
- Mitogen-Activated Protein Kinase Kinase 2 Inhibitors
- P-glycoprotein substrates
- Protein Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- UGT1A1 Substrates
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as benzimidazoles. These are organic compounds containing a benzene ring fused to an imidazole ring (five member ring containing a nitrogen atom, 4 carbon atoms, and two double bonds).
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Benzimidazoles
- Sub Class
- Not Available
- Direct Parent
- Benzimidazoles
- Alternative Parents
- Aniline and substituted anilines / Bromobenzenes / Chlorobenzenes / Aryl bromides / Aryl chlorides / Aryl fluorides / N-substituted imidazoles / Vinylogous amides / Heteroaromatic compounds / Amino acids and derivatives show 9 more
- Substituents
- Alcohol / Amine / Amino acid or derivatives / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Aryl bromide / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle show 25 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 6UH91I579U
- CAS number
- 606143-52-6
- InChI Key
- CYOHGALHFOKKQC-UHFFFAOYSA-N
- InChI
- InChI=1S/C17H15BrClFN4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26)
- IUPAC Name
- 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-1,3-benzodiazole-6-carboxamide
- SMILES
- CN1C=NC2=C(F)C(NC3=C(Cl)C=C(Br)C=C3)=C(C=C12)C(=O)NOCCO
References
- General References
- Seto T, Hirai F, Saka H, Kogure Y, Yoh K, Niho S, Fukase K, Shimada H, Sasai M, Fukino K: Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer. Jpn J Clin Oncol. 2018 Jan 1;48(1):31-42. doi: 10.1093/jjco/hyx144. [Article]
- Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P: Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. Clin Ther. 2016 Nov;38(11):2447-2458. doi: 10.1016/j.clinthera.2016.09.002. Epub 2016 Oct 15. [Article]
- Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC: Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943. [Article]
- Holt SV, Logie A, Odedra R, Heier A, Heaton SP, Alferez D, Davies BR, Wilkinson RW, Smith PD: The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. Br J Cancer. 2012 Feb 28;106(5):858-66. doi: 10.1038/bjc.2012.8. Epub 2012 Feb 16. [Article]
- Tchernev G, Chokoeva AA, Patterson JW, Bakardzhiev I, Wollina U, Tana C: Plexiform Neurofibroma: A Case Report. Medicine (Baltimore). 2016 Feb;95(6):e2663. doi: 10.1097/MD.0000000000002663. [Article]
- Ciombor KK, Bekaii-Saab T: Selumetinib for the treatment of cancer. Expert Opin Investig Drugs. 2015 Jan;24(1):111-123. doi: 10.1517/13543784.2015.982275. Epub 2014 Nov 11. [Article]
- McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. doi: 10.1016/j.bbamcr.2006.10.001. Epub 2006 Oct 7. [Article]
- Abrams SL, Steelman LS, Shelton JG, Wong EW, Chappell WH, Basecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA: The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle. 2010 May;9(9):1781-91. doi: 10.4161/cc.9.9.11483. Epub 2010 May 10. [Article]
- Dry JR, Pavey S, Pratilas CA, Harbron C, Runswick S, Hodgson D, Chresta C, McCormack R, Byrne N, Cockerill M, Graham A, Beran G, Cassidy A, Haggerty C, Brown H, Ellison G, Dering J, Taylor BS, Stark M, Bonazzi V, Ravishankar S, Packer L, Xing F, Solit DB, Finn RS, Rosen N, Hayward NK, French T, Smith PD: Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Res. 2010 Mar 15;70(6):2264-73. doi: 10.1158/0008-5472.CAN-09-1577. Epub 2010 Mar 9. [Article]
- Zhou Y, Lin S, Tseng KF, Han K, Wang Y, Gan ZH, Min DL, Hu HY: Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells. BMC Cancer. 2016 Oct 21;16(1):818. doi: 10.1186/s12885-016-2773-4. [Article]
- Li C, Chen Z, Yang H, Luo F, Chen L, Cai H, Li Y, You G, Long D, Li S, Zhang Q, Rao L: Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway. PLoS One. 2016 Jul 20;11(7):e0159079. doi: 10.1371/journal.pone.0159079. eCollection 2016. [Article]
- Dymond AW, Martin P, So K, Huang Y, Severin P, Holmes V, Mariani G, Marbury T: Pharmacokinetics of a Single Oral Dose of the MEK1/2 Inhibitor Selumetinib in Subjects With End-Stage Renal Disease or Varying Degrees of Hepatic Impairment Compared With Healthy Subjects. J Clin Pharmacol. 2017 May;57(5):592-605. doi: 10.1002/jcph.848. Epub 2016 Dec 26. [Article]
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- NIH National Cancer Institute: Clinical Trials Using Selumetinib [Link]
- Health Canada Approved Drug Products: KOSELUGO (Selumetinib) Oral Capsules [Link]
- FDA: FDA approves selumetinib for neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas [Link]
- External Links
- Human Metabolome Database
- HMDB0304858
- KEGG Drug
- D09666
- PubChem Compound
- 10127622
- PubChem Substance
- 347828055
- ChemSpider
- 8303141
- BindingDB
- 50355497
- 2289380
- ChEBI
- 90227
- ChEMBL
- CHEMBL1614701
- ZINC
- ZINC000031773258
- PharmGKB
- PA166129529
- PDBe Ligand
- 3EW
- Wikipedia
- Selumetinib
- PDB Entries
- 4u7z / 7jut / 7juz / 7m0t
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 Approved for Marketing Not Available NF type1 With Inoperable Plexiform Neurofibromas 1 somestatus stop reason just information to hide Not Available Completed Treatment Thyroid Cancer 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Locally Advanced or Metastatic Non Small Cell Lung Cancer Stage IIIb - IV 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Neurofibromatosis, type 1 (von Recklinghausen's disease) / Plexiform Neurofibroma 1 somestatus stop reason just information to hide 3 Completed Treatment Metastatic / Uveal Melanoma 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 10 mg/1 Capsule Oral 10 mg Capsule Oral 25 mg/1 Capsule Oral 25 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8178693 No 2012-05-15 2023-03-13 US US9562017 No 2017-02-07 2026-12-12 US US7425637 No 2008-09-16 2024-04-11 US US9156795 No 2015-10-13 2026-12-12 US US11813246 No 2009-03-26 2029-03-26 US
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.021 mg/mL ALOGPS logP 3.24 ALOGPS logP 4.27 Chemaxon logS -4.3 ALOGPS pKa (Strongest Acidic) 10.26 Chemaxon pKa (Strongest Basic) 5.07 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 88.41 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 102.61 m3·mol-1 Chemaxon Polarizability 40.61 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
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-0000900000-67bc6d5da41378bce0d1 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-000x-0008900000-33bd57d3114c6b4fde40 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-06si-0008900000-c7b30e789cef09a869e1 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0pdi-0049100000-c8789e3a156486291b5e Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-002f-7009500000-f57d820222c651910787 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-9000000000-308ba3122a7cc4b1a574 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]- 178.50569 predictedDeepCCS 1.0 (2019) [M+H]+ 180.8637 predictedDeepCCS 1.0 (2019) [M+Na]+ 187.51344 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126). Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis
- Specific Function
- ATP binding
- Gene Name
- MAP2K1
- Uniprot ID
- Q02750
- Uniprot Name
- Dual specificity mitogen-activated protein kinase kinase 1
- Molecular Weight
- 43438.65 Da
References
- Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, Marlow A, Hurley B, Lyssikatos J, Lee PA, Winkler JD, Koch K, Wallace E: Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007 Mar 1;13(5):1576-83. doi: 10.1158/1078-0432.CCR-06-1150. [Article]
- Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD: AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007 Aug;6(8):2209-19. doi: 10.1158/1535-7163.MCT-07-0231. [Article]
- Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC: Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943. [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]
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF dimerization and BRAF activation (PubMed:29433126)
- Specific Function
- ATP binding
- Gene Name
- MAP2K2
- Uniprot ID
- P36507
- Uniprot Name
- Dual specificity mitogen-activated protein kinase kinase 2
- Molecular Weight
- 44423.735 Da
References
- Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, Marlow A, Hurley B, Lyssikatos J, Lee PA, Winkler JD, Koch K, Wallace E: Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007 Mar 1;13(5):1576-83. doi: 10.1158/1078-0432.CCR-06-1150. [Article]
- Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD: AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007 Aug;6(8):2209-19. doi: 10.1158/1535-7163.MCT-07-0231. [Article]
- Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC: Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med. 2016 Dec 29;375(26):2550-2560. doi: 10.1056/NEJMoa1605943. [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]
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Dymond AW, Elks C, Martin P, Carlile DJ, Mariani G, Lovick S, Huang Y, Lorch U, Brown H, So K: Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis. Eur J Clin Pharmacol. 2017 Jun;73(6):717-726. doi: 10.1007/s00228-017-2217-3. Epub 2017 Mar 10. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P: Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. Clin Ther. 2016 Nov;38(11):2447-2458. doi: 10.1016/j.clinthera.2016.09.002. Epub 2016 Oct 15. [Article]
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P: Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. Clin Ther. 2016 Nov;38(11):2447-2458. doi: 10.1016/j.clinthera.2016.09.002. Epub 2016 Oct 15. [Article]
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P: Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. Clin Ther. 2016 Nov;38(11):2447-2458. doi: 10.1016/j.clinthera.2016.09.002. Epub 2016 Oct 15. [Article]
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P: Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. Clin Ther. 2016 Nov;38(11):2447-2458. doi: 10.1016/j.clinthera.2016.09.002. Epub 2016 Oct 15. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids (PubMed:10553002, PubMed:18577768). 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:10553002, PubMed:18577768). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates fatty acids specifically at the omega-1 position displaying the highest catalytic activity for saturated fatty acids (PubMed:10553002, PubMed:18577768). May be involved in the oxidative metabolism of xenobiotics (Probable)
- Specific Function
- 4-nitrophenol 2-monooxygenase activity
- Gene Name
- CYP2E1
- Uniprot ID
- P05181
- Uniprot Name
- Cytochrome P450 2E1
- Molecular Weight
- 56848.42 Da
References
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Dymond AW, Elks C, Martin P, Carlile DJ, Mariani G, Lovick S, Huang Y, Lorch U, Brown H, So K: Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis. Eur J Clin Pharmacol. 2017 Jun;73(6):717-726. doi: 10.1007/s00228-017-2217-3. Epub 2017 Mar 10. [Article]
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- 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:15472229, PubMed:18674515, PubMed:18719240, PubMed:23288867, PubMed:23756265, PubMed:24641623). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:23756265). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229, PubMed:18719240, PubMed:23288867). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption (PubMed:23756265). Involved in the glucuronidation of calcidiol, which is the major circulating form of vitamin D3, essential for the regulation of calcium and phosphate homeostasis (PubMed:24641623). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonists losartan, candesartan and zolarsartan, which can inhibit the effect of angiotensin II (PubMed:18674515)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A3
- Uniprot ID
- P35503
- Uniprot Name
- UDP-glucuronosyltransferase 1A3
- Molecular Weight
- 60337.835 Da
References
- Dymond AW, Howes C, Pattison C, So K, Mariani G, Savage M, Mair S, Ford G, Martin P: Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. Clin Ther. 2016 Nov;38(11):2447-2458. doi: 10.1016/j.clinthera.2016.09.002. Epub 2016 Oct 15. [Article]
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Carrier
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Carrier
- General Function
- Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
Components:
References
- FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
- de Gooijer MC, Zhang P, Weijer R, Buil LCM, Beijnen JH, van Tellingen O: The impact of P-glycoprotein and breast cancer resistance protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors. Int J Cancer. 2018 Jan 15;142(2):381-391. doi: 10.1002/ijc.31052. Epub 2017 Oct 4. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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
- de Gooijer MC, Zhang P, Weijer R, Buil LCM, Beijnen JH, van Tellingen O: The impact of P-glycoprotein and breast cancer resistance protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors. Int J Cancer. 2018 Jan 15;142(2):381-391. doi: 10.1002/ijc.31052. Epub 2017 Oct 4. [Article]
- Dymond AW, Elks C, Martin P, Carlile DJ, Mariani G, Lovick S, Huang Y, Lorch U, Brown H, So K: Pharmacokinetics and pharmacogenetics of the MEK1/2 inhibitor, selumetinib, in Asian and Western healthy subjects: a pooled analysis. Eur J Clin Pharmacol. 2017 Jun;73(6):717-726. doi: 10.1007/s00228-017-2217-3. Epub 2017 Mar 10. [Article]
Drug created at October 20, 2016 20:40 / Updated at February 10, 2024 11:21