Selumetinib

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 signaling 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 tumors 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 tumors in the nervous system.3,5 Some patients with this disorder develop plexiform neurofibromas (PN); however, this is considered to be relatively uncommon compared to other variants of NF-1.5 Luckily, the use of selumetinib in patients with NF-1 has shown efficacy in shrinking associated tumors and is linked to other positive clinical outcomes.3

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
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

Although selumetinib has been investigated for the treatment of several types of cancer, it is currently only indicated for the treatment of neurofibromatosis type 1 (NF1) in patients ≥2 years who have symptomatic, inoperable plexiform neurofibromas (PN).6,13,14

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
ADual specificity mitogen-activated protein kinase kinase 1
inhibitor
Humans
ADual specificity mitogen-activated protein kinase kinase 2
inhibitor
Humans
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
Adverseeffects
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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.
DrugInteraction
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Selumetinib.
AbametapirThe serum concentration of Selumetinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Selumetinib can be increased when combined with Abatacept.
AbemaciclibAbemaciclib may decrease the excretion rate of Selumetinib which could result in a higher serum level.
AbirateroneThe serum concentration of Selumetinib can be increased when it is combined with Abiraterone.
AcalabrutinibThe metabolism of Selumetinib can be decreased when combined with Acalabrutinib.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Selumetinib.
AcetaminophenSelumetinib may increase the hepatotoxic activities of Acetaminophen.
AcetohexamideThe metabolism of Selumetinib can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Selumetinib can be decreased when combined with Acetyl sulfisoxazole.
Interactions
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Food Interactions
  • Take on an empty stomach. Avoid consuming food 2 hours before and 1 hour after each dose.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Selumetinib sulfate807ME4B7IJ943332-08-9GRKFGZYYYYISDX-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KoselugoCapsule25 mg/1OralAstraZeneca Pharmaceuticals LP2020-04-16Not applicableUS flag
KoselugoCapsule10 mg/1OralAstraZeneca Pharmaceuticals LP2020-04-16Not applicableUS flag

Categories

Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
  14. NIH National Cancer Institute: Clinical Trials Using Selumetinib [Link]
KEGG Drug
D09666
PubChem Compound
10127622
PubChem Substance
347828055
ChemSpider
8303141
BindingDB
50355497
RxNav
2289380
ChEBI
90227
ChEMBL
CHEMBL1614701
ZINC
ZINC000031773258
PharmGKB
PA166129529
PDBe Ligand
3EW
Wikipedia
Selumetinib
PDB Entries
4u7z / 7jut / 7juz / 7m0t
FDA label
Download (2.01 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentLocally Advanced or Metastatic Non Small Cell Lung Cancer Stage IIIb - IV1
3CompletedTreatmentMelanoma, Uveal / Metastatic1
3RecruitingTreatmentLow Grade Astrocytomas / Low Grade Glioma (LGG) / Metastatic Low Grade Astrocytoma / Metastatic Low Grade Glioma1
3RecruitingTreatmentLow Grade Glioma (LGG) / Neurofibromatosis Type 1 (NF1) / Visual Pathway Glioma1
3RecruitingTreatmentNeurofibromatosis Type 1 (NF1) / Plexiform Neurofibromas (PN)1
3RecruitingTreatmentRecurrent Low Grade Astrocytoma / Recurrent WHO Grade II Glioma / Refractory Low Grade Astrocytoma / Refractory Low Grade Glioma / Refractory WHO Grade I Glioma1
3TerminatedTreatmentDifferentiated Thyroid Cancer (DTC)1
2Active Not RecruitingTreatmentAdvanced Malignant Solid Neoplasm / Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma / Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma / Recurrent Childhood Central Nervous System Neoplasm / Recurrent Childhood Non-Hodgkin Lymphoma / Recurrent Malignant Solid Neoplasm / Recurrent Neuroblastoma / Refractory Malignant Solid Neoplasm / Refractory Neuroblastoma / Refractory Non-Hodgkin's lymphoma / Refractory, primary Central Nervous System Neoplasm1
2Active Not RecruitingTreatmentBiliary Tract Carcinoma / Carcinoma of Gallbladder1
2Active Not RecruitingTreatmentLocally Advanced or Metastatic Non Small Cell Lung Cancer Stage IIIb - IV1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral10 mg/1
CapsuleOral25 mg/1
CapsuleOral10 mg
CapsuleOral25 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8178693No2012-05-152023-03-13US flag
US9562017No2017-02-072026-12-12US flag
US7425637No2008-09-162024-04-11US flag
US9156795No2015-10-132026-12-12US flag

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.021 mg/mLALOGPS
logP3.24ALOGPS
logP4.27ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)10.26ChemAxon
pKa (Strongest Basic)5.07ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area88.41 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity102.61 m3·mol-1ChemAxon
Polarizability40.61 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Receptor signaling protein tyrosine phosphatase activity
Specific 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 t...
Gene Name
MAP2K1
Uniprot ID
Q02750
Uniprot Name
Dual specificity mitogen-activated protein kinase kinase 1
Molecular Weight
43438.65 Da
References
  1. 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]
  2. 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]
  3. 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]
  4. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Scaffold protein binding
Specific 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).
Gene Name
MAP2K2
Uniprot ID
P36507
Uniprot Name
Dual specificity mitogen-activated protein kinase kinase 2
Molecular Weight
44423.735 Da
References
  1. 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]
  2. 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]
  3. 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]
  4. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. 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
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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]
  2. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. 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]
  2. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. 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]
  2. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. 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
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. 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]
  2. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
References
  1. 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]
  2. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Carrier
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Carrier
General Function
Not Available
Specific Function
Functions as 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...

Components:
References
  1. FDA Approved Drug Products: Koselugo (selumetinib) capsules for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. 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
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. 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]
  2. 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 on October 20, 2016 20:40 / Updated on October 09, 2021 02:49