Binimetinib

Details

Stereochemistry	ACHIRAL
Molecular Formula	C17H15BrF2N4O3
Molecular Weight	441.227
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(F)C=C(Br)C=C3)=C(C=C12)C(=O)NOCCO

InChI

InChIKey=ACWZRVQXLIRSDF-UHFFFAOYSA-N

InChI=1S/C17H15BrF2N4O3/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://www.arraybiopharma.com/product-pipeline/binimetinib/
Curator's Comment: https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&code=C84865 | https://www.ncbi.nlm.nih.gov/pubmed/23635776 | https://acr.confex.com/acr/2006/webprogram/Paper5558.html

Binimetinib (MEK162) is an oral small-molecule with potential antineoplastic activity. It is a selective mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, a key protein kinase in the RAS/RAF/MEK/ERK pathway, which regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis. Inappropriate activation of this pathway has been shown to occur in many cancers, in particular through mutations in BRAF, KRAS and NRAS. MEK162 at 6 mg/kg, BID combined with BEZ235 (dual PI3K/mTOR inhibitor) resulted in a significant reduction of tumor growth in immunodeficient mice injected with MCF7 cells. There are three ongoing Phase 3 trials with binimetinib in advanced cancer patients: NEMO (NRAS-mutant melanoma), COLUMBUS (encorafenib in combination with binimetinib in BRAF-mutant melanoma) and BEACON CRC (encorafenib, binimetinib and cetuximab in BRAF-mutant colorectal cancer).

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Mitogen-activated protein kinase kinase kinase 1 1 Target ID: CHEMBL3956 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27149444 \| https://www.ncbi.nlm.nih.gov/pubmed/25937299	Inhibitor 8297		12.0 nM [IC50]
Dual specificity mitogen-activated protein kinase kinase 2 9 Target ID: CHEMBL2964 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27149444 \| https://www.ncbi.nlm.nih.gov/pubmed/25937299	Inhibitor 8297		12.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Metastatic or unresectable cutaneous melanoma 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf	Primary		Approved 8429	MEKTOVI Approved Use is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test Launch Date 2018
BRAF V600E-mutant metastatic colorectal cancer 1 Sources: https://clinicaltrials.gov/ct2/show/NCT02928224	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
545 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28152546	60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BINIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
241 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28152546	45 mg 2 times / day multiple, oral dose: 45 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BINIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1710 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28152546	60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BINIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
964 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28152546	45 mg 2 times / day multiple, oral dose: 45 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BINIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
80 mg 2 times / day steady, oral Highest studied dose Dose: 80 mg, 2 times / day Route: oral Route: steady Dose: 80 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/	unhealthy, 58 years (range: 30–86 years) n = 4 Health Status: unhealthy Condition: biliary cancer\| KRAS-mutant colorectal cancer Age Group: 58 years (range: 30–86 years) Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/	DLT: Chorioretinopathy, Dermatitis acneiform... Disc. AE: Macular oedema, Nausea... Other AEs: Retinal deposits, Retinopathy... Dose limiting toxicities: Chorioretinopathy (grade 3, 25%) Dermatitis acneiform (grade 3, 25%) AEs leading to discontinuation/dose reduction: Macular oedema (grade 3-4, 25%) Nausea (grade 1-2, 25%) Vomiting (grade 1-2, 50%) Fatigue (grade 1-2, 25%) Other AEs: Retinal deposits (grade 3-4, 25%) Retinopathy (grade 3-4, 25%) Papilloedema (grade 3-4, 25%) Retinal detachment (grade 3-4, 25%) Retinal disorder (grade 3-4, 25%) Acne (grade 3-4, 25%) Skin exfoliation (grade 3-4, 25%) Diarrhoea (grade 1-2, 25%) Peripheral oedema (grade 1-2, 50%) Abdominal pain (grade 1-2, 25%) Anorexia (grade 1-2, 25%) Dyspnoea (grade 1-2, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/
60 mg 2 times / day steady, oral MTD Dose: 60 mg, 2 times / day Route: oral Route: steady Dose: 60 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/	unhealthy, 58 years (range: 30–86 years) n = 41 Health Status: unhealthy Condition: biliary cancer\| KRAS-mutant colorectal cancer Age Group: 58 years (range: 30–86 years) Sex: M+F Population Size: 41 Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/	Disc. AE: Dermatitis acneiform, Acne... Other AEs: Diarrhoea, Peripheral oedema... AEs leading to discontinuation/dose reduction: Dermatitis acneiform (grade 1-2, 85%) Acne (grade 1-2, 85%) Skin exfoliation (grade 1-2, 85%) Dermatitis acneiform (grade 3-4, 2%) Acne (grade 3-4, 2%) Skin exfoliation (grade 3-4, 2%) Nausea (grade 1-2, 51%) Vomiting (grade 1-2, 49%) Fatigue (grade 1-2, 39%) Fatigue (grade 3-4, 2%) Other AEs: Diarrhoea (grade 1-2, 61%) Peripheral oedema (grade 1-2, 51%) Anaemia (grade 1-2, 12%) Anaemia (grade 3-4, 24%) Abdominal pain (grade 1-2, 17%) Abdominal pain (grade 3-4, 7%) Anorexia (grade 1-2, 20%) Constipation (grade 1-2, 20%) Constipation (grade 3-4, 5%) Dyspnoea (grade 1-2, 15%) Dyspnoea (grade 3-4, 2%) Pyrexia (grade 1-2, 17%) Pyrexia (grade 3-4, 2%) Dizziness (grade 1-2, 22%) Pulmonary embolism (grade 4, 1 patient) Generalised oedema (grade 4, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/
60 mg 2 times / day steady, oral MTD Dose: 60 mg, 2 times / day Route: oral Route: steady Dose: 60 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf https://pubmed.ncbi.nlm.nih.gov/28152546	unhealthy, 58 years (range: 30–86 years) n = 41 Health Status: unhealthy Condition: biliary cancer\| KRAS-mutant colorectal cancer Age Group: 58 years (range: 30–86 years) Sex: M+F Population Size: 41 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf https://pubmed.ncbi.nlm.nih.gov/28152546	Disc. AE: Retinal deposits, Retinopathy... Other AEs: Papilloedema, Retinal disorder... AEs leading to discontinuation/dose reduction: Retinal deposits (grade 1-2, 27%) Retinopathy (grade 1-2, 27%) Chorioretinopathy (grade 1-2, 27%) Macular oedema (grade 1-2, 27%) Retinal detachment (grade 1-2, 27%) Other AEs: Papilloedema (grade 1-2, 27%) Retinal disorder (grade 1-2, 27%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf https://pubmed.ncbi.nlm.nih.gov/28152546
45 mg 2 times / day steady, oral RP2D Dose: 45 mg, 2 times / day Route: oral Route: steady Dose: 45 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/	unhealthy, 58 years (range: 30–86 years) n = 44 Health Status: unhealthy Condition: biliary cancer\| KRAS-mutant colorectal cancer Age Group: 58 years (range: 30–86 years) Sex: M+F Population Size: 44 Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/	Disc. AE: Chorioretinopathy, Macular oedema... Other AEs: Retinal deposits, Retinopathy... AEs leading to discontinuation/dose reduction: Chorioretinopathy (grade 1-2, 11%) Macular oedema (grade 1-2, 11%) Retinal detachment (grade 1-2, 11%) Dermatitis acneiform (grade 1-2, 75%) Acne (grade 1-2, 75%) Skin exfoliation (grade 1-2, 75%) Dermatitis acneiform (grade 3-4, 2%) Acne (grade 3-4, 2%) Skin exfoliation (grade 3-4, 2%) Nausea (grade 1-2, 61%) Vomiting (grade 1-2, 52%) Diarrhoea (grade 1-2, 39%) Fatigue (grade 1-2, 41%) Fatigue (grade 3-4, 5%) Other AEs: Retinal deposits (grade 1-2, 11%) Retinopathy (grade 1-2, 11%) Papilloedema (grade 1-2, 11%) Retinal disorder (grade 1-2, 11%) Peripheral oedema (grade 1-2, 45%) Anaemia (grade 1-2, 11%) Anaemia (grade 3-4, 7%) Abdominal pain (grade 1-2, 16%) Abdominal pain (grade 3-4, 2%) Anorexia (grade 1-2, 18%) Constipation (grade 1-2, 14%) Dyspnoea (grade 1-2, 11%) Dyspnoea (grade 3-4, 5%) Pyrexia (grade 1-2, 16%) Dizziness (grade 1-2, 11%) Sources: https://pubmed.ncbi.nlm.nih.gov/28152546/
45 mg 2 times / day steady, oral Recommended Dose: 45 mg, 2 times / day Route: oral Route: steady Dose: 45 mg, 2 times / day Co-administed with:: encorafenib(450 mg once daily) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf	unhealthy n = 192 Health Status: unhealthy Condition: BRAF V600 mutation-positive unresectable or metastatic melanoma Population Size: 192 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf	Disc. AE: Left ventricular dysfunction, Serous retinopathy... Other AEs: Fatigue, Pyrexia... AEs leading to discontinuation/dose reduction: Left ventricular dysfunction (6%) Serous retinopathy (5%) Left ventricular dysfunction (3%) Serous retinopathy (3%) Colitis (2%) Hemorrhage (2%) Headache (1%) Other AEs: Fatigue (grade 3-4, 3%) Pyrexia (grade 3-4, 4%) Peripheral edema (grade 3-4, 1%) Fatigue (all grades, 43%) Pyrexia (all grades, 18%) Peripheral edema (all grades, 13%) Nausea (grade 3-4, 2%) Diarrhea (grade 3-4, 3%) Vomiting (grade 3-4, 2%) Abdominal pain (grade 3-4, 4%) Nausea (all grades, 41%) Diarrhea (all grades, 36%) Vomiting (all grades, 30%) Abdominal pain (all grades, 28%) Constipation (all grades, 22%) Rash (grade 3-4, 1%) Rash (all grades, 22%) Dizziness (grade 3-4, 3%) Dizziness (all grades, 15%) Visual impairment (all grades, 20%) Serous retinopathy (grade 3-4, 3%) Serous retinopathy (all grades, 20%) Hemorrhage (grade 3-4, 3%) Hemorrhage (all grades, 19%) Hypertension (grade 3-4, 6%) Hypertension (all grades, 11%) Anemia (grade 3-4, 3.6%) Anemia (all grades, 36%) Leukopenia (all grades, 13%) Lymphopenia (grade 3-4, 2.1%) Lymphopenia (all grades, 13%) Neutropenia (grade 3-4, 3.1%) Neutropenia (all grades, 13%) Creatinine increased (grade 3-4, 3.6%) Creatinine increased (all grades, 93%) Creatine phosphokinase increased (grade 3-4, 5%) Creatine phosphokinase increased (all grades, 58%) Gamma-glutamyltransferase increased (grade 3-4, 11%) Gamma-glutamyltransferase increased (all grades, 45%) ALT increased (grade 3-4, 6%) ALT increased (all grades, 29%) AST increased (grade 3-4, 2.6%) AST increased (all grades, 27%) Alkaline phosphatase increased (grade 3-4, 0.5%) Alkaline phosphatase increased (all grades, 21%) Hyponatremia (grade 3-4, 3.6%) Hyponatremia (all grades, 18%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inducer 389 inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT2 647 UGT1A 3 CYP1A2 1524 CYP2A6 707 CYP2C8 911 CYP2C19 1478 CYP2E1 882 CYP3A4/5 278 CYP2B6 810	CYP1A1 349 CYP1A2 1054 CYP2C19 991 P-gp 1537 BCRP 561 UGT 192 UGT1A1 418 OCT1 327 OATP1B1 406 OATP1B3 350 OATP2B1 104

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2A6 739	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	no
CYP2C8 965	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	no
CYP2E1 970	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	no
CYP3A4/5 335	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	no
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=61 Page: -	weak [IC50 18.1 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	weak [IC50 50 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	weak [IC50 50 uM]
UGT1A 5	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=61 Page: -	weak [IC50 >25 uM]
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=61 Page: -	weak	unlikely Comment: It is not expected for binimetinib to have a clinically relevant induction of CYP2C9, as the plasma concentrations observed in patients is well below the concentration required for minimal induction of CYP2C9 based on in vitro study Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=61 Page: -
CYP2B6 1001	inhibitor 3277 Sources: https://www.ema.europa.eu/en/documents/assessment-report/mektovi-epar-public-assessment-report_en.pdf#page=30 Page: -	yes [IC50 6 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A1 349	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=41 Page: -	major
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=41 Page: -	major
UGT 192	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=41 Page: -	major
UGT1A1 418	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=54 Page: -	major	no (co-administration study) Comment: atazanavir did not alter the exposure of BINIMETINIB Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=54 Page: -
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=41 Page: -	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=59 Page: -	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=59 Page: -	no
OATP2B1 104	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=59 Page: -	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=59 Page: -	no
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=41 Page: -	no	no (co-administration study) Comment: did not alter the exposure of midazolam Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=41 Page: -
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=59 Page: -	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=59 Page: -	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210498Orig1s000MultidisciplineR.pdf#page=33 Page: -

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:145371	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:145371
ChemicalBook	CB82604200	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB82604200
MolPort	MolPort-028-720-357	https://www.molport.com/shop/molecule-link/MolPort-028-720-357
ZINC	ZINC000038460704	http://zinc15.docking.org/substances/ZINC000038460704

PubMed

Title	Date	PubMed
RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer.	2013 Jun	23635776

Patents

Sample Use Guides

In Vivo Use Guide

MEK162 administered as a fixed dose of 45 mg (3 x 15 mg tablets) BID, with a glass of water and taken with or without food.

Route of Administration: Oral

In Vitro Use Guide

MCF7 (mutant PIK3CA) breast cancer cells exhibiting sensitivity to PI3K inhibition were seeded in 12-well plates (2 × 10^4). After 24 hours, cells were treated with BEZ235, BKM120, GDC-0941, or MK2206 alone or in combination with MEK162. MEK162 (1 uM) combined with MK-2206 (2 mM) completely reversed the resistance of RSK-expressing MCF7 cells.

Name

Type

Language

Binimetinib

Official Name

English

1H-Benzimidazole-6-carboxamide, 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-

Systematic Name

English

binimetinib [INN]

Common Name

English

BINIMETINIB [USAN]

Common Name

English

BINIMETINIB [JAN]

Common Name

English

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

Systematic Name

English

MEK162

Code

English

Binimetinib [WHO-DD]

Common Name

English

ARRY-438162

Code

English

MEKTOVI

Brand Name

English

BINIMETINIB [MI]

Common Name

English

NVP-MEK162

Code

English

ARRY-162

Code

English

BINIMETINIB [ORANGE BOOK]

Common Name

English

6-[(4-bromo-2-fluorophenyl)amino]-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide

Systematic Name

English

MEK-162

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

440414