SELUMETINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C17H15BrClFN4O3
Molecular Weight	457.6815
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cn1cnc2c1cc(c(c2F)Nc3ccc(cc3Cl)Br)C(=NOCCO)O

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:: 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 17 Target ID: CHEMBL3587 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17332304	Inhibitor 7701	Non-small cell lung cancer Thyroid cancer Uveal melanoma	14 nM [IC50]
Dual specificity mitogen-activated protein kinase kinase 2 8 Target ID: CHEMBL2964 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17332304	Inhibitor 7701	Non-small cell lung cancer Thyroid cancer Uveal melanoma	14 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase
Non-small cell lung cancer 195 Sources: http://adisinsight.springer.com/drugs/800019504	Primary	Dual specificity mitogen-activated protein kinase kinase 1 Dual specificity mitogen-activated protein kinase kinase 2	Phase III 650
Thyroid cancer 16 Sources: http://adisinsight.springer.com/drugs/800019504	Primary	Dual specificity mitogen-activated protein kinase kinase 2 Dual specificity mitogen-activated protein kinase kinase 1	Phase III 650
Uveal melanoma 7 Sources: http://adisinsight.springer.com/drugs/800019504	Primary	Dual specificity mitogen-activated protein kinase kinase 1 Dual specificity mitogen-activated protein kinase kinase 2	Phase III 650

C_max

Value	Dose	Co-administered	Analyte	Population
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	Co-administered	Analyte	Population
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	Co-administered	Analyte	Population
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://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412920/			SELUMETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN 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 experiment_type: steady dose_type: Recommended co-adm with data_source: 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) population: unhealthy age: 10.2 years (range: 3.5 - 17.4 years) sex: M+F food_status: n: data_source: 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%) data_source: 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 experiment_type: steady dose_type: Recommended co-adm with data_source: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213756s000lbl.pdf	unhealthy, 10.2 years (range: 3.5 - 17.4 years) population: unhealthy age: 10.2 years (range: 3.5 - 17.4 years) sex: M+F food_status: n: data_source: 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) data_source: 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 experiment_type: steady dose_type: co-adm with data_source: https://pubmed.ncbi.nlm.nih.gov/20179232	unhealthy, 57.9 years (range: 30-76 years) population: unhealthy age: 57.9 years (range: 30-76 years) sex: M+F food_status: n: data_source: https://pubmed.ncbi.nlm.nih.gov/20179232	DLT: Acneiform dermatitis, Pleural effusion... Dose limiting toxicities: Acneiform dermatitis (grade 3) Pleural effusion (grade 3) data_source: https://pubmed.ncbi.nlm.nih.gov/20179232
75 mg 2 times / day steady, oral dose: 75 mg 2 times / day route: oral experiment_type: steady dose_type: co-adm with data_source: https://pubmed.ncbi.nlm.nih.gov/20179232	unhealthy, 57.9 years (range: 30-76 years) population: unhealthy age: 57.9 years (range: 30-76 years) sex: M+F food_status: n: data_source: https://pubmed.ncbi.nlm.nih.gov/20179232	DLT: Fatigue... Dose limiting toxicities: Fatigue (grade 3) data_source: 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 experiment_type: steady dose_type: Highest studied dose co-adm with data_source: https://pubmed.ncbi.nlm.nih.gov/18390968	unhealthy, 58 years (range: 29–78 years) population: unhealthy age: 58 years (range: 29–78 years) sex: M+F food_status: n: data_source: 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) data_source: https://pubmed.ncbi.nlm.nih.gov/18390968

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 657 inhibitor 1172 substrate 1470	inhibitor 1318 substrate 865	inhibitor 1421	inhibitor 1360

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 574 CYP1A2 1268 CYP2A6 594 CYP2B6 679 CYP2C19 1215 CYP2C8 761 CYP2E1 761 P-gp 1089 UGT1A1 174 UGT2B7 130 OATP1B1 698 OATP1B3 613 OCT1 473 OCT2 582 MATE1 290 MATE2 258	BCRP 461 CYP1A2 892 CYP2C19 830 CYP2E1 567 P-gp 1223 UGT1A1 358 UGT1A3 358	CYP1A2 618 CYP2B6 486 MATE1 4 MATE2 4 OAT1 24 OATP1B1 23 OATP1B3 6 OCT2 5

Drug as perpetrator

Target	Modality	Activity
CYP2A6 625	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	no
CYP2E1 841	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	no
MATE1 291	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 105, 107	no
MATE2 258	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 105, 107	no
OCT1 488	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327, 238	no
OCT2 583	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 105, 107	no
CYP2D6 1455	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 45.3 uM]
CYP2C8 810	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 52.1 uM]
UGT1A1 219	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327	weak [IC50 >100 uM]
UGT2B7 138	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327	weak [IC50 >100 uM]
CYP1A2 1406	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 >70 uM]
CYP2B6 845	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 >70 uM]
CYP2C19 1277	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 >70 uM]
CYP2C9 1362	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101, 327	weak [IC50 >70 uM]
CYP3A4 1462	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327	weak [IC50 >70 uM]
BCRP 639	inhibitor 2614 Sources: https://pubmed.ncbi.nlm.nih.gov/28921565/	weak
CYP1A2 1406	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
CYP2B6 845	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
CYP3A4 1462	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
MATE1 291	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
MATE2 258	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
OAT1 551	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
OATP1B1 713	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
OATP1B3 622	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
OCT2 583	inducer 1333 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
P-gp 1255	inhibitor 2614 Sources: https://pubmed.ncbi.nlm.nih.gov/28921565/	weak
OATP1B3 622	inhibitor 2614 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 327, 238	yes [IC50 19 uM]
OATP1B1 713	inhibitor 2614 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 461	substrate 2752 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 100	weak
CYP1A2 892	substrate 2752 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
CYP2C9 865	substrate 2752 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
CYP2E1 567	substrate 2752 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 101	weak
P-gp 1223	substrate 2752 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 100, 328	weak
UGT1A1 358	substrate 2752 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 92, 101	yes
UGT1A3 358	substrate 2752 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 92, 101	yes
CYP2C19 830	substrate 2752 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 1470	substrate 2752 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 1392	inhibitor 1374 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000MultidisciplineR.pdf Page: 50

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:90227	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:90227
MolPort	MolPort-009-679-426	https://www.molport.com/shop/molecule-link/MolPort-009-679-426
ZINC	ZINC000031773258	http://zinc15.docking.org/substances/ZINC000031773258

PubMed

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
Blockade of MEK signaling potentiates 5-Aza-2'-deoxycytidine-induced apoptosis and upregulation of p21(waf1) in acute myelogenous leukemia cells.	2009 Sep 1	19422044
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
Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma.	2011 Sep 25	21946352
The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition.	2012 Apr 10	22415236
Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification.	2012 Jul	22729845
Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.	2012 May 8	22569000
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

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

Systematic Name

English

ARRY-886

Code

English

AZD6244

Code

English

SELUMETINIB [INN]

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 [WHO-DD]

Common Name

English

SELUMETINIB [USAN]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/18/2050