SELUMETINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C17H15BrClFN4O3
Molecular Weight	457.681
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CN1C=NC2=C(F)C(NC3=CC=C(Br)C=C3Cl)=C(C=C12)C(=O)NOCCO

InChI

InChIKey=CYOHGALHFOKKQC-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C17H15BrClFN4O3
Molecular Weight	457.681
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Selumetinib (AZD6244 or ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of Ras-Raf-mitogen-activated protein kinase kinase (MEK1/2). This inhibition can prevent ERK activation, disrupt downstream signal transduction, and inhibit cancer cell proliferation and survival. Selumetinib has shown tumour suppressive activity in multiple rodent models of human cancer including melanoma, pancreatic, colon, lung, and breast cancers. AstraZeneca is responsible for development and commercialization of selumetinib.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dual specificity mitogen-activated protein kinase kinase 1 20	Inhibitor 8,297		14.0 nM [IC50]
Dual specificity mitogen-activated protein kinase kinase 2 9	Inhibitor 8,297		14.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 206	Primary	Phase III 656	Unknown
Thyroid cancer 16	Primary	Phase III 656	Unknown
Uveal melanoma 7	Primary	Phase III 656	Unknown

C_max

Value	Dose	Analyte	Population
1207 ng/mL	75 mg single, oral	SELUMETINIB plasma	Homo sapiens
863 ng/mL	50 mg single, oral	SELUMETINIB plasma	Homo sapiens
647 ng/mL	100 mg single, oral	SELUMETINIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
6335 ng × h/mL	75 mg single, oral	SELUMETINIB plasma	Homo sapiens
2620 ng × h/mL	50 mg single, oral	SELUMETINIB plasma	Homo sapiens
3299 ng × h/mL	100 mg single, oral	SELUMETINIB plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
5.33 h	75 mg single, oral	SELUMETINIB plasma	Homo sapiens
7.34 h	50 mg single, oral	SELUMETINIB plasma	Homo sapiens
10 h	100 mg single, oral	SELUMETINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.4%	50 mg single, oral		SELUMETINIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
25 mg/m2 2 times / day steady, oral Recommended	unhealthy, 10.2 years (range: 3.5 - 17.4 years)	Disc. AE: Creatinine increased, Weight increased...
25 mg/m2 2 times / day steady, oral Recommended	unhealthy, 10.2 years (range: 3.5 - 17.4 years)	Disc. AE: Vomiting, Paronychia...
100 mg 2 times / day steady, oral	unhealthy, 57.9 years (range: 30-76 years)	DLT: Acneiform dermatitis, Pleural effusion...
75 mg 2 times / day steady, oral	unhealthy, 57.9 years (range: 30-76 years)	DLT: Fatigue...
300 mg 2 times / day steady, oral Highest studied dose	unhealthy, 58 years (range: 29–78 years)	Other AEs: Dermatitis acneiform, Rash...

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AEs

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AE	Significance	Dose	Population
Acute kidney injury	2% Disc. AE	25 mg/m2 2 times / day steady, oral Recommended	unhealthy, 10.2 years (range: 3.5 - 17.4 years)
Creatinine increased	2% Disc. AE	25 mg/m2 2 times / day steady, oral Recommended	unhealthy, 10.2 years (range: 3.5 - 17.4 years)
Diarrhea	2% Disc. AE	25 mg/m2 2 times / day steady, oral Recommended	unhealthy, 10.2 years (range: 3.5 - 17.4 years)
Malignant peripheral nerve sheath tumor	2% Disc. AE	25 mg/m2 2 times / day steady, oral Recommended	unhealthy, 10.2 years (range: 3.5 - 17.4 years)
Paronychia	2% Disc. AE	25 mg/m2 2 times / day steady, oral Recommended	unhealthy, 10.2 years (range: 3.5 - 17.4 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 inhibitor 1,587 substrate 1,737	inhibitor 1,767 substrate 1,037	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C19 1,478 CYP2C8 911 CYP2E1 882 P-gp 1,461 UGT1A1 204 UGT2B7 146 OATP1B1 788 OATP1B3 706 OCT1 512 OCT2 647 MATE1 306 MATE2 263	BCRP 561 CYP1A2 1,054 CYP2C19 991 CYP2E1 667 P-gp 1,537 UGT1A1 418 UGT1A3 422	CYP1A2 701 CYP2B6 547 MATE1 6 MATE2 5 OAT1 26 OATP1B1 26 OATP1B3 6 OCT2 6

Drug as perpetrator

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Target	Modality	Activity
CYP2A6 739	inhibitor 3,277	no
CYP2E1 970	inhibitor 3,277	no
MATE1 308	inhibitor 3,277	no
MATE2 263	inhibitor 3,277	no
OCT1 543	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity
BCRP 561	substrate 3,367	weak
CYP1A2 1,054	substrate 3,367	weak
CYP2C9 1,037	substrate 3,367	weak
CYP2E1 667	substrate 3,367	weak
P-gp 1,537	substrate 3,367	weak

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90227	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90227
ChemicalBook	CB81871940	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB81871940
eMolecules	31507604	https://www.emolecules.com/cgi-bin/more?vid=31507604
MolPort	MolPort-009-679-426	https://www.molport.com/shop/molecule-link/MolPort-009-679-426
Selleck Chemicals	AZD6244	http://www.selleckchem.com/products/AZD6244.html

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PubMed

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Title	Date	PubMed
		252160213
Mutations of the BRAF gene in human cancer.	2002 Jun 27	12068308
Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma.	2007 Jan	17237274
Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor.	2007 Mar 1	17332304
AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma.	2007 Sep	17876044

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Patents

Sample Use Guides

In Vivo Use Guide

Oral selumetinib (50, 100 and 200mg bid for 28-day cycles) was well tolerated in patients with refractory solid tumours. The maximum tolerated dose was established to be 200mg bid. 100 mg dose of selumetinib proved to be more tolerable than the 200mg dose over prolonged periods. The 100mg dose has been chosen for phase II studies.

Route of Administration: Oral

In Vitro Use Guide

The sensitivity of a large panel of cell lines to Selumetinib (AZD6244 or ARRY-142886) was evaluated in vitro and correlated with RAS and BRAF gene mutation status. There was a wide range of sensitivity to AZD6244 from highly sensitive (IC50, <100 nmol/L) to highly resistant (>10 μmol/L)

Substance Class	Chemical
Record UNII	6UH91I579U
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

SELUMETINIB

Official Name

English

5-[(4-Bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide

Systematic Name

English

SELUMETINIB [MI]

Common Name

English

ARRY-886

Code

English

AZD6244

Code

English

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Classification Tree

Code System

Code

Positive

EU-Orphan Drug

EU/3/18/2050

Protein Kinase Inhibitor

NCI_THESAURUS

C69145

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Designated/Withdrawn

FDA ORPHAN DRUG

475815

Designated/Approved

FDA ORPHAN DRUG

624017

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Code System

Code

Type

Description

RXCUI

2289380

PRIMARY

INN

9078

PRIMARY

EPA CompTox

DTXSID3048944

PRIMARY

SMS_ID

100000124313

PRIMARY

CAS

606143-52-6

PRIMARY

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CYTOCHROME P450 2C19

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PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Comments:

IN VITRO

Interaction Type:

BINDING

Amount:

98.4 % (average)


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SELUMETINIB

EXCRETED UNCHANGED

Comments:

After a single oral dose of radiolabeled selumetinib 75 mg (1.5 times the recommended dose) to healthy adults

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL

Amount:

19 % (average)

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2-((6-(4-BROMO-2-CHLORO-ANILINO)-7-FLUORO-3H-BENZIMIDAZOLE-5-CARBONYL)AMINO)OXYACETIC ACID

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URINE

Amount:

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Amount:

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METABOLITE -> PARENT

Qualification:

FECAL

Amount:

3 % (average)


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N-DESMETHYL SELUMETINIB

METABOLITE ACTIVE -> PARENT

Qualification:

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Amount:

6 % (average)


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METABOLITE -> PARENT

Qualification:

FECAL; URINE

Amount:

2 % (average)

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Related Record

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SELUMETINIB

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
Tmax	PHARMACOKINETIC	[1 to 1.5] hours (average)	AT STEADY-STATE IN PEDIATRIC PATIENTS

Tmax	PHARMACOKINETIC	[2.5 to 3] hours (average)	IN HEALTHY ADULTS HIGH-FAT MEAL SINGLE DOSE ADMINISTRATION 75 mg (average)

Volume of Distribution	PHARMACOKINETIC	[78 to 171] LITERS (average)	IN PEDIATRIC PATIENTS

Tmax	PHARMACOKINETIC	[1.9 to 2.4] hours (average)	IN HEALTHY ADULTS SINGLE DOSE ADMINISTRATION 50 mg (average) LOW-FAT MEAL

ORAL BIOAVAILABILITY	PHARMACOKINETIC	62 % (average)	IN HEALTHY ADULTS

Biological Half-life	PHARMACOKINETIC	6.2 hours (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator