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

Structure Search

SMILES

CN1C=NC2=C(F)C(NC3=C(Cl)C=C(Br)C=C3)=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

Description
Sources: http://adisinsight.springer.com/drugs/800019504
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/17332304

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 Target ID: CHEMBL3587 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17332304	Inhibitor 8504		14.0 nM [IC50]
Dual specificity mitogen-activated protein kinase kinase 2 10 Target ID: CHEMBL2964 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17332304	Inhibitor 8504		14.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 211 Sources: http://adisinsight.springer.com/drugs/800019504	Primary	Phase III 665	Unknown Approved Use Unknown
Thyroid cancer 17 Sources: http://adisinsight.springer.com/drugs/800019504	Primary	Phase III 665	Unknown Approved Use Unknown
Uveal melanoma 7 Sources: http://adisinsight.springer.com/drugs/800019504	Primary	Phase III 665	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
1207 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20179232/	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
863 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28019010/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
647 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/21519015	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
6335 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20179232/	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2620 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28019010/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3299 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/21519015	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
5.33 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20179232/	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
7.34 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28019010/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
10 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/21519015	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	SELUMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.4% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28019010/	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:		SELUMETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
25 mg/m2 2 times / day steady, oral Recommended Dose: 25 mg/m2, 2 times / day Route: oral Route: steady Dose: 25 mg/m2, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf	unhealthy, 10.2 years (range: 3.5 - 17.4 years) Health Status: unhealthy Age Group: 10.2 years (range: 3.5 - 17.4 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf	Disc. AE: Creatinine increased, Weight increased... AEs leading to discontinuation/dose reduction: Creatinine increased (2%) Weight increased (2%) Diarrhea (2%) Paronychia (2%) Malignant peripheral nerve sheath tumor (2%) Acute kidney injury (2%) Skin ulcer (2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf
25 mg/m2 2 times / day steady, oral Recommended Dose: 25 mg/m2, 2 times / day Route: oral Route: steady Dose: 25 mg/m2, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf	unhealthy, 10.2 years (range: 3.5 - 17.4 years) Health Status: unhealthy Age Group: 10.2 years (range: 3.5 - 17.4 years) Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf	Disc. AE: Vomiting, Paronychia... AEs leading to discontinuation/dose reduction: Vomiting (>5) Paronychia (>5) Diarrhea (>5) Nausea (>5) Abdominal pain (>5) Rash (>5) Skin infection (>5) Influenza like illness (>5) Pyrexia (>5) Weight gain (>5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf
100 mg 2 times / day steady, oral Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20179232	unhealthy, 57.9 years (range: 30-76 years) Health Status: unhealthy Age Group: 57.9 years (range: 30-76 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/20179232	DLT: Acneiform dermatitis, Pleural effusion... Dose limiting toxicities: Acneiform dermatitis (grade 3) Pleural effusion (grade 3) Sources: https://pubmed.ncbi.nlm.nih.gov/20179232
75 mg 2 times / day steady, oral Dose: 75 mg, 2 times / day Route: oral Route: steady Dose: 75 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20179232	unhealthy, 57.9 years (range: 30-76 years) Health Status: unhealthy Age Group: 57.9 years (range: 30-76 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/20179232	DLT: Fatigue... Dose limiting toxicities: Fatigue (grade 3) Sources: https://pubmed.ncbi.nlm.nih.gov/20179232
300 mg 2 times / day steady, oral Highest studied dose Dose: 300 mg, 2 times / day Route: oral Route: steady Dose: 300 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18390968	unhealthy, 58 years (range: 29–78 years) Health Status: unhealthy Age Group: 58 years (range: 29–78 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/18390968	Other AEs: Dermatitis acneiform, Rash... Other AEs: Dermatitis acneiform (grade 3-4, 2 patients) Rash (grade 3-4, 2 patients) Rash erythematous (grade 3-4, 2 patients) Rash maculo-papular (grade 3-4, 2 patients) Rash pruritic (grade 3-4, 2 patients) Diarrhea (grade 3-4, 1 patient) Nausea (grade 1-2, 3 patients) Fatigue (grade 1-2, 2 patients) Peripheral edema (grade 1-2, 2 patients) Vomiting (grade 1-2, 2 patients) Blurred vision (grade 1-2, 3 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/18390968

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 inhibitor 2252 substrate 1946	inhibitor 2438 substrate 1193	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 CYP1A2 2153 CYP2A6 879 CYP2B6 926 CYP2C19 2057 CYP2C8 1057 CYP2E1 1060 P-gp 1741 UGT1A1 246 UGT2B7 197 OATP1B1 1079 OATP1B3 961 OCT1 620 OCT2 779 MATE1 415 MATE2 267	BCRP 697 CYP1A2 1197 CYP2C19 1119 CYP2E1 729 P-gp 2052 UGT1A1 479 UGT1A3 470	CYP1A2 832 CYP2B6 669 MATE1 5 MATE2 2 OAT1 28 OATP1B1 29 OATP1B3 8 OCT2 5

Drug as perpetrator

Target	Modality	Activity
CYP2A6 911	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	no
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	no
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 105, 107	no
MATE2 267	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 105, 107	no
OCT1 656	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327, 238	no
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 105, 107	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 45.3 uM]
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 52.1 uM]
UGT1A1 303	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327.0	weak [IC50 >100 uM]
UGT2B7 210	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327.0	weak [IC50 >100 uM]
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 >70 uM]
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 >70 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 >70 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 >70 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327.0	weak [IC50 >70 uM]
BCRP 985	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/28921565/	weak
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
MATE1 416	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
MATE2 267	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
OAT1 730	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
OATP1B1 1095	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
OATP1B3 970	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
OCT2 782	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
P-gp 1932	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/28921565/	weak
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327, 238	yes [IC50 19 uM]
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327, 238	yes [IC50 8.76 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 100.0	weak
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
CYP2E1 729	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101.0	weak
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 100, 328	weak
UGT1A1 479	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 92, 101	yes
UGT1A3 470	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 92, 101	yes
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 107	yes	yes (co-administration study) Comment: fluconazole increased selumetinib AUC by 53% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 107
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 92, 101, 106	yes	yes (co-administration study) Comment: itraconazole increased selumetinib AUC by 49%; fluconazole increased selumetinib exposure 50%; rifampicin reduced selumetinib exposure 51%; erythromycin increased selumetinib AUC by 40%; efavirenz reduced selumetinib AUC by 40% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 92, 101, 106

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 50.0

Sourcing

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
ZINC	ZINC000031773258	http://zinc15.docking.org/substances/ZINC000031773258

PubMed

Title	Date	PubMed
		252160213
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378
Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification.	2012 Jul	22729845
MEK and the inhibitors: from bench to bedside.	2013 Apr 12	23587417
Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL-6-activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells.	2013 Sep 1	23782265
Synergistic induction of human cathelicidin antimicrobial peptide gene expression by vitamin D and stilbenoids.	2014 Mar	24039193

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)

Name

Type

Language

SELUMETINIB

Official Name

English

selumetinib [INN]

Preferred 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

Selumetinib [WHO-DD]

Common Name

English

AZD-6244

Code

English

1H-BENZIMIDAZOLE-6-CARBOXAMIDE, 5-((4-BROMO-2-CHLOROPHENYL)AMINO)-4-FLUORO-N-(2- HYDROXYETHOXY)-1-METHYL-

Common Name

English

SELUMETINIB [USAN]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/18/2050