Identification

Summary

Cobimetinib is an antineoplastic agent and selective inhibitor of the mitogen-activated extracellular kinase (MEK) pathway used to treat unresectable or metastatic melanoma.

Brand Names
Cotellic
Generic Name
Cobimetinib
DrugBank Accession Number
DB05239
Background

Cobimetinib is an orally active, potent and highly selective small molecule inhibiting mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), and central components of the RAS/RAF/MEK/ERK signal transduction pathway. It has been approved in Switzerland and the US, in combination with vemurafenib for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 531.318
Monoisotopic: 531.06306
Chemical Formula
C21H21F3IN3O2
Synonyms
  • Cobimetinib
External IDs
  • GDC 0973
  • GDC-0973
  • GDC0973
  • RG 7420
  • RG-7420
  • RG7420
  • RO5514041
  • XL 518
  • XL-518
  • XL518

Pharmacology

Indication

For the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Cobimetinib is used in combination with vemurafenib, a BRAF inhibitor.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 1 (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signalling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors becomes BRAF-inhibitor resistant due to reactivation of MAPK signalling. BRAF-inhibitor resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK.

Mechanism of action

MEK inhibitor Cobimetinib specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway.

TargetActionsOrganism
ADual specificity mitogen-activated protein kinase kinase 1
inhibitor
Humans
Absorption

The bioavailability of cobimetinib is 46%, the AUC and Cmax is unaffected by food.

Volume of distribution

806L in cancer patients based on a population PK analysis.

Protein binding

95% bound to human plasma protein.

Metabolism

Cobimetinib is mainly metabolized via CYP3A oxidation and UGT2B7 glucuronidation with no major metabolites formed.

Route of elimination

76% of the dose was recovered in feces with 6.6% as unchanged drug. 17.8% of the dose was recovered in urine with 1.6% as unchanged drug.

Half-life

Average half life was 44 hours.

Clearance

13.9L/h

Adverse Effects
Adverseeffects
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Toxicity

The most common adverse effects (>20%) for cobimetinib are diarrhea, photosensitivity reactions, nausea, fever and vomiting.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of Cobimetinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Cobimetinib can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Cobimetinib.
AbirateroneThe metabolism of Cobimetinib can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Cobimetinib can be decreased when combined with Acalabrutinib.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Cobimetinib.
AcetaminophenThe metabolism of Cobimetinib can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Cobimetinib can be decreased when combined with Acetazolamide.
AcetylcysteineThe excretion of Cobimetinib can be decreased when combined with Acetylcysteine.
AdalimumabThe metabolism of Cobimetinib can be increased when combined with Adalimumab.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits the metabolism of cobimetinib through the CYP3A4 pathway and, therefore, may increase serum levels of cobimetinib.
  • Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of cobimetinib.
  • Take with or without food. Cobimetinib bioavailability is unaffected by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Cobimetinib fumarate6EXI96H8SV1369665-02-0RESIMIUSNACMNW-BXRWSSRYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CotellicTablet, film coated20 mg/1mgOralDelpharm Milano Srl2015-11-102018-02-16US flag
CotellicTablet20 mgOralHoffmann La Roche2016-04-06Not applicableCanada flag
CotellicTablet, film coated20 mg/1OralGenentech, Inc.2015-11-10Not applicableUS flag
CotellicTablet, film coated20 mgOralRoche Registration Gmb H2020-12-23Not applicableEU flag

Categories

ATC Codes
L01XE38 — Cobimetinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as anthranilamides. These are aromatic compound containing a benzene carboxamide moiety that carries an amine group at the 2-position of the benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Anthranilamides
Alternative Parents
2-aminobenzamides / 3-halobenzoic acids and derivatives / 4-halobenzoic acids and derivatives / Aniline and substituted anilines / Benzoyl derivatives / Iodobenzenes / Fluorobenzenes / Piperidines / Aryl fluorides / Aryl iodides
show 13 more
Substituents
1,2-aminoalcohol / 2-aminobenzamide / 3-halobenzoic acid or derivatives / 4-halobenzoic acid or derivatives / Alcohol / Amine / Amino acid or derivatives / Aminobenzamide / Aminobenzoic acid or derivatives / Aniline or substituted anilines
show 31 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
ER29L26N1X
CAS number
934660-93-2
InChI Key
BSMCAPRUBJMWDF-KRWDZBQOSA-N
InChI
InChI=1S/C21H21F3IN3O2/c22-14-6-5-13(19(18(14)24)27-16-7-4-12(25)9-15(16)23)20(29)28-10-21(30,11-28)17-3-1-2-8-26-17/h4-7,9,17,26-27,30H,1-3,8,10-11H2/t17-/m0/s1
IUPAC Name
1-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl}-3-[(2S)-piperidin-2-yl]azetidin-3-ol
SMILES
OC1(CN(C1)C(=O)C1=C(NC2=C(F)C=C(I)C=C2)C(F)=C(F)C=C1)[C@@H]1CCCCN1

References

General References
  1. Garnock-Jones KP: Cobimetinib: First Global Approval. Drugs. 2015 Oct;75(15):1823-30. doi: 10.1007/s40265-015-0477-8. [Article]
  2. Han K, Jin JY, Marchand M, Eppler S, Choong N, Hack SP, Tikoo N, Bruno R, Dresser M, Musib L, Budha NR: Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors. Cancer Chemother Pharmacol. 2015 Nov;76(5):917-24. doi: 10.1007/s00280-015-2862-0. Epub 2015 Sep 13. [Article]
  3. Singh A, Ruan Y, Tippett T, Narendran A: Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells. J Exp Clin Cancer Res. 2015 Sep 18;34:104. doi: 10.1186/s13046-015-0222-x. [Article]
  4. Tran KA, Cheng MY, Mitra A, Ogawa H, Shi VY, Olney LP, Kloxin AM, Maverakis E: MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy. Drug Des Devel Ther. 2015 Dec 21;10:43-52. doi: 10.2147/DDDT.S93545. eCollection 2016. [Article]
  5. Takahashi RH, Choo EF, Ma S, Wong S, Halladay J, Deng Y, Rooney I, Gates M, Hop CE, Khojasteh SC, Dresser MJ, Musib L: Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans. Drug Metab Dispos. 2016 Jan;44(1):28-39. doi: 10.1124/dmd.115.066282. Epub 2015 Oct 8. [Article]
KEGG Drug
D10405
PubChem Compound
16222096
PubChem Substance
310264856
ChemSpider
17349374
BindingDB
50391802
RxNav
1722365
ChEBI
90851
ChEMBL
CHEMBL2146883
ZINC
ZINC000060325170
PharmGKB
PA166160044
PDBe Ligand
EUI
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Cobimetinib
PDB Entries
4an2 / 4lmn / 7juy / 7m0v
FDA label
Download (324 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentDisease or R Group Histiocytoses1
3Active Not RecruitingTreatmentMalignant Melanoma of Skin1
3CompletedTreatmentAdvanced BRAFV600 Wild-type Melanoma1
3CompletedTreatmentColorectal Cancer1
3CompletedTreatmentMelanoma, Malignant1
3WithdrawnTreatmentMalignant Melanoma of Skin1
2Active Not RecruitingTreatmentAppendix Adenocarcinoma / Locally Advanced Malignant Neoplasm / Locally Advanced Skin Squamous Cell Carcinoma / Metastatic Malignant Neoplasm / Metastatic Skin Squamous Cell Carcinoma / Metastatic Small Intestinal Adenocarcinoma / Rare Lesion / Rare Neoplastic Syndrome / Refractory Malignant Neoplasm / Squamous Cell Skin Carcinoma / Stage IV Small Intestinal Adenocarcinoma AJCC v8 / Unresectable Malignant Neoplasm1
2Active Not RecruitingTreatmentBiliary Cancers / Bladder Cancer, Cancer / Neoplasms / Salivary Cancer / Solid Tumors1
2Active Not RecruitingTreatmentBRAF V600 mutation / Stage IV Malignant Melanoma / Tumors Metastatic to Brain1
2Active Not RecruitingTreatmentCarcinoma of Gallbladder / Stage IV Intrahepatic Cholangiocarcinoma AJCC v8 / Unresectable Cholangiocarcinoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral20 mg
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral20 mg/1mg
Tablet, film coatedOral
Tablet, coatedOral20 mg
Tablet, film coatedOral20 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8362002No2013-01-292026-10-05US flag
US7803839No2010-09-282027-02-01US flag
US10478400No2019-11-192036-06-29US flag
US10590102No2020-03-172036-06-30US flag
US11087354No2014-06-222034-06-22US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0422 mg/mLALOGPS
logP3.35ALOGPS
logP5.04ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)13.37ChemAxon
pKa (Strongest Basic)9.76ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area64.6 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity115.85 m3·mol-1ChemAxon
Polarizability44.75 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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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. Singh A, Ruan Y, Tippett T, Narendran A: Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells. J Exp Clin Cancer Res. 2015 Sep 18;34:104. doi: 10.1186/s13046-015-0222-x. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Singh A, Ruan Y, Tippett T, Narendran A: Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells. J Exp Clin Cancer Res. 2015 Sep 18;34:104. doi: 10.1186/s13046-015-0222-x. [Article]
  2. Budha NR, Ji T, Musib L, Eppler S, Dresser M, Chen Y, Jin JY: Evaluation of Cytochrome P450 3A4-Mediated Drug-Drug Interaction Potential for Cobimetinib Using Physiologically Based Pharmacokinetic Modeling and Simulation. Clin Pharmacokinet. 2016 Nov;55(11):1435-1445. doi: 10.1007/s40262-016-0412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Choo EF, Ly J, Chan J, Shahidi-Latham SK, Messick K, Plise E, Quiason CM, Yang L: Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib. Mol Pharm. 2014 Nov 3;11(11):4199-207. doi: 10.1021/mp500435s. Epub 2014 Oct 3. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Weak inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Singh A, Ruan Y, Tippett T, Narendran A: Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells. J Exp Clin Cancer Res. 2015 Sep 18;34:104. doi: 10.1186/s13046-015-0222-x. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. Singh A, Ruan Y, Tippett T, Narendran A: Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells. J Exp Clin Cancer Res. 2015 Sep 18;34:104. doi: 10.1186/s13046-015-0222-x. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Weak inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Choo EF, Ly J, Chan J, Shahidi-Latham SK, Messick K, Plise E, Quiason CM, Yang L: Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib. Mol Pharm. 2014 Nov 3;11(11):4199-207. doi: 10.1021/mp500435s. Epub 2014 Oct 3. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created at October 21, 2007 22:24 / Updated at December 05, 2021 19:51