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 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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Selumetinib (DB11689)

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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

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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

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Neurofibromatosis type 1 (nf1)		••••••••••••	•••••••••	•••••••••••• •••••••••• ••••••••• •••••••••••••	•••••••

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Contraindications & Blackbox Warnings

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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

Target	Actions	Organism
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

• Selumetinib
  • M15 (AZ13326637)
  • M14 (AZ12791138)
    • M2 (amide glucuronide selumetinib metabolite)
      • M1 selumetinib metabolite
      • M6 selumetinib metabolite
    • M12 (Primary amide, N-demethylated selumetinib metabolite)
      • M10 selumetinib metabolite
        • M1 selumetinib metabolite
      • M13 (Primary amide, N-demethylated, mono-oxidized selumetinib metabolite)
      • M9 (ribose conjugated selumetinib metabolite)
    • M15 (AZ13326637)
  • M8 (N-desmethyl selumetinib)
    • M5 (glucuronidated N-desmethyl selumetinib)
    • M3 (glucuronidated N-desmethyl selumetinib)
    • M11 (N-demethylated carboxylic acid selumetinib metabolite)
    • M12 (Primary amide, N-demethylated selumetinib metabolite)
      • M10 selumetinib metabolite
        • M1 selumetinib metabolite
      • M13 (Primary amide, N-demethylated, mono-oxidized selumetinib metabolite)
      • M9 (ribose conjugated selumetinib metabolite)
  • M4 (glucuronidated selumetinib)
  • M7 (glucuronidated selumetinib)

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

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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

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Not Available

Interactions

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abametapir	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.

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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
Koselugo	Capsule	10 mg	Oral	Alexion Pharma Gmbh	2023-01-03	Not applicable
Koselugo	Capsule	10 mg	Oral	Astra Zeneca Ab	2021-10-25	Not applicable
Koselugo	Capsule	25 mg/1	Oral	AstraZeneca Pharmaceuticals LP	2020-04-16	Not applicable
Koselugo	Capsule	25 mg	Oral	Alexion Pharma Gmbh	2023-01-03	Not applicable

Categories

ATC Codes

L01EE04 — Selumetinib

• L01EE — Mitogen-activated protein kinase (MEK) inhibitors
• L01E — PROTEIN KINASE INHIBITORS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

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 / Secondary amines / Azacyclic compounds / Hydrocarbon derivatives / Organic oxides / Organobromides / Organochlorides / Organofluorides / Organopnictogen compounds / Primary alcohols

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Substituents

Alcohol / Amine / Amino acid or derivatives / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Aryl bromide / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Benzimidazole / Bromobenzene / Carboxylic acid derivative / Chlorobenzene / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Monocyclic benzene moiety / N-substituted imidazole / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organobromide / Organochloride / Organofluoride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Primary alcohol / Secondary amine / Vinylogous amide

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]
15. Health Canada Approved Drug Products: KOSELUGO (Selumetinib) Oral Capsules [Link]
16. 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

RxNav

2289380

ChEBI

90227

ChEMBL

CHEMBL1614701

ZINC

ZINC000031773258

PharmGKB

PA166129529

PDBe Ligand

3EW

Wikipedia

Selumetinib

PDB Entries

4u7z / 7jut / 7juz / 7m0t

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Locally Advanced or Metastatic Non Small Cell Lung Cancer Stage IIIb - IV	1
3	Active Not Recruiting	Treatment	Neurofibromatosis, type 1 (von Recklinghausen's disease) / Plexiform Neurofibroma	1
3	Completed	Treatment	Metastatic / Uveal Melanoma	1
3	Recruiting	Treatment	Low Grade Astrocytomas / Low-Grade Glioma / Metastatic Low Grade Astrocytomas / Metastatic Low Grade Glioma (LGG)	1
3	Recruiting	Treatment	Low-Grade Glioma / Neurofibromatosis, type 1 (von Recklinghausen's disease) / Visual Pathway Glioma	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral	10 mg
Capsule	Oral	10 mg/1
Capsule	Oral	25 mg
Capsule	Oral	25 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8178693	No	2012-05-15	2023-03-13
US9562017	No	2017-02-07	2026-12-12
US7425637	No	2008-09-16	2024-04-11
US9156795	No	2015-10-13	2026-12-12
US11813246	No	2009-03-26	2029-03-26

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	predicted	DeepCCS 1.0 (2019)
[M+H]+	180.8637	predicted	DeepCCS 1.0 (2019)
[M+Na]+	187.51344	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Dual specificity mitogen-activated protein kinase kinase 1

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]

Details2. Dual specificity mitogen-activated protein kinase kinase 2

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]

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Drug created at October 20, 2016 20:40 / Updated at February 10, 2024 11:21