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Identification
NameCobimetinib
Accession NumberDB05239
TypeSmall Molecule
GroupsApproved
Description

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.

Structure
Thumb
SynonymsNot Available
External Identifiers
  • XL-518
  • GDC 0973
  • GDC-0973
  • GDC0973
  • RG 7420
  • RG-7420
  • RG7420
  • RO5514041
  • XL 518
  • XL518
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cotellictablet, film coated20 mg/1oralGenentech, Inc.2015-11-10Not applicableUs
Cotellictablet20 mgoralHoffmann La Roche Limited2016-04-06Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Cobimetinib fumarate
1369665-02-0
Thumb
  • InChI Key: RESIMIUSNACMNW-BXRWSSRYSA-N
  • Monoisotopic Mass: 1178.13707
  • Average Mass: 1178.707
DBSALT001290
Categories
UNIIER29L26N1X
CAS number934660-93-2
WeightAverage: 531.318
Monoisotopic: 531.06306
Chemical FormulaC21H21F3IN3O2
InChI KeyBSMCAPRUBJMWDF-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
Taxonomy
ClassificationNot classified
Pharmacology
IndicationFor 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.
PharmacodynamicsCobimetinib 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 actionMEK 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.
Related Articles
AbsorptionThe 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 binding95% bound to human plasma protein.
Metabolism

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

Route of elimination76% 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 lifeAverage half life was 44 hours.
Clearance

13.9L/h

ToxicityThe most common adverse effects (>20%) for cobimetinib are diarrhea, photosensitivity reactions, nausea, fever and vomiting.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral20 mg
Tablet, film coatedoral20 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7803839 No2007-02-012027-02-01Us
US8362002 No2006-10-052026-10-05Us
Properties
StateSolid
Experimental PropertiesNot 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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Garnock-Jones KP: Cobimetinib: First Global Approval. Drugs. 2015 Oct;75(15):1823-30. doi: 10.1007/s40265-015-0477-8. [PubMed:26452567 ]
  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. [PubMed:26365290 ]
  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. [PubMed:26384788 ]
  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. [PubMed:26730180 ]
  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. [PubMed:26451002 ]
External Links
ATC CodesNot Available
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (324 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
BexaroteneThe serum concentration of Cobimetinib can be decreased when it is combined with Bexarotene.
ConivaptanThe serum concentration of Cobimetinib can be increased when it is combined with Conivaptan.
DasatinibThe serum concentration of Cobimetinib can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Cobimetinib can be decreased when it is combined with Deferasirox.
FluconazoleThe serum concentration of Cobimetinib can be increased when it is combined with Fluconazole.
FosaprepitantThe serum concentration of Cobimetinib can be increased when it is combined with Fosaprepitant.
Fusidic AcidThe serum concentration of Cobimetinib can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of Cobimetinib can be increased when it is combined with Idelalisib.
IvacaftorThe serum concentration of Cobimetinib can be increased when it is combined with Ivacaftor.
LuliconazoleThe serum concentration of Cobimetinib can be increased when it is combined with Luliconazole.
NelfinavirThe serum concentration of Cobimetinib can be increased when it is combined with Nelfinavir.
OsimertinibThe serum concentration of Cobimetinib can be increased when it is combined with Osimertinib.
PalbociclibThe serum concentration of Cobimetinib can be increased when it is combined with Palbociclib.
PhenytoinThe serum concentration of Cobimetinib can be decreased when it is combined with Phenytoin.
PorfimerCobimetinib may increase the photosensitizing activities of Porfimer.
SiltuximabThe serum concentration of Cobimetinib can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Cobimetinib can be increased when it is combined with Simeprevir.
StiripentolThe serum concentration of Cobimetinib can be increased when it is combined with Stiripentol.
TocilizumabThe serum concentration of Cobimetinib can be decreased when it is combined with Tocilizumab.
VerteporfinCobimetinib may increase the photosensitizing activities of Verteporfin.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
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 to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2...
Gene Name:
MAP2K1
Uniprot ID:
Q02750
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. [PubMed:26384788 ]

Enzymes

Kind
Protein group
Organism
Human
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Components:
NameUniProt IDDetails
Cytochrome P450 3A4P08684 Details
Cytochrome P450 3A43Q9HB55 Details
Cytochrome P450 3A5P20815 Details
Cytochrome P450 3A7P24462 Details
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. [PubMed:26384788 ]
Kind
Protein
Organism
Human
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
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. [PubMed:25243894 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateweak 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, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:
SLCO1B1
Uniprot ID:
Q9Y6L6
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. [PubMed:26384788 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateweak 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), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:
SLCO1B3
Uniprot ID:
Q9NPD5
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. [PubMed:26384788 ]
Kind
Protein
Organism
Human
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 from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
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. [PubMed:25243894 ]
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Drug created on October 21, 2007 16:24 / Updated on July 25, 2016 01:56