Identification

Name
Cobimetinib
Accession Number
DB05239
Type
Small Molecule
Groups
Approved, Investigational
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
Synonyms
Not Available
External IDs
XL-518 / GDC 0973 / GDC-0973 / GDC0973 / RG 7420 / RG-7420 / RG7420 / RO5514041 / XL 518 / XL518
Product Ingredients
IngredientUNIICASInChI Key
Cobimetinib fumarate6EXI96H8SV1369665-02-0RESIMIUSNACMNW-BXRWSSRYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CotellicTablet20 mgOralHoffmann La Roche2016-04-06Not applicableCanada
CotellicTablet, film coated20 mg/1OralGenentech, Inc.2015-11-10Not applicableUs
CotellicTablet, film coated20 mg/1mgOralDelpharm Milano Srl2015-11-10Not applicableUs
Categories
UNII
ER29L26N1X
CAS number
934660-93-2
Weight
Average: 531.318
Monoisotopic: 531.06306
Chemical Formula
C21H21F3IN3O2
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

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.

Associated Conditions
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
Human
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

Toxicity

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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenThe serum concentration of Cobimetinib can be increased when it is combined with Acetaminophen.
Acetyl sulfisoxazoleThe serum concentration of Cobimetinib can be increased when it is combined with Acetyl sulfisoxazole.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Cobimetinib.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Cobimetinib.
AlclometasoneThe metabolism of Cobimetinib can be decreased when combined with Alclometasone.
AlfuzosinThe metabolism of Cobimetinib can be decreased when combined with Alfuzosin.
AmcinonideThe metabolism of Cobimetinib can be decreased when combined with Amcinonide.
AmiodaroneThe serum concentration of Cobimetinib can be increased when it is combined with Amiodarone.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Cobimetinib.
AmlodipineThe serum concentration of Cobimetinib can be increased when it is combined with Amlodipine.
Food Interactions
Not Available

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. [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
KEGG Drug
D10405
PubChem Compound
16222096
PubChem Substance
310264856
ChemSpider
17349374
BindingDB
50391802
ChEBI
90851
ChEMBL
CHEMBL2146883
PharmGKB
PA166160044
HET
EUI
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Cobimetinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
4an2 / 4lmn
FDA label
Download (324 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentMalignant Melanoma of Skin / Melanoma (Skin) / Skin Cancers / Skin Carcinoma1
1Active Not RecruitingTreatmentColorectal Cancers1
1Active Not RecruitingTreatmentMalignant Melanoma1
1Active Not RecruitingTreatmentTumors, Solid1
1CompletedNot AvailableHealthy Participants / Healthy Volunteers1
1CompletedNot AvailableHealthy Volunteers3
1CompletedBasic ScienceHealthy Volunteers2
1CompletedTreatmentHealthy Volunteers1
1CompletedTreatmentMalignant Melanoma1
1CompletedTreatmentNeoplasms2
1CompletedTreatmentNon-Small Cell Lung Cancer, Metastatic Colorectal Cancer, Metastatic Non Small Cell Lung Cancer, Metastatic Cancers, Melanoma1
1CompletedTreatmentTumors, Solid1
1RecruitingTreatmentLocally Advanced Solid Tumors / Metastatic Solid Tumors1
1RecruitingTreatmentMalignant Melanoma1
1RecruitingTreatmentMelanoma1
1RecruitingTreatmentMelanoma / Skin Cancers1
1TerminatedTreatmentSolid Cancers / Tumors, Solid1
1WithdrawnTreatmentNeoplasms1
1, 2Active Not RecruitingTreatmentAdvanced or Metastatic Solid Tumors1
1, 2RecruitingTreatmentAdenocarcinoma of the Pancreas1
1, 2RecruitingTreatmentEstrogen Receptor-positive / HER2/Neu Negative / Stage III Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
1, 2RecruitingTreatmentGastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
1, 2RecruitingTreatmentMelanoma1
1, 2RecruitingTreatmentMultiple Myeloma (MM)1
1, 2RecruitingTreatmentSolid or Brain Tumor With Evidence of RAS/RAF/MEK/ERK Activation / Tumors, Solid1
1, 2RecruitingTreatmentTriple Negative Breast Cancer (TNBC)1
2Active Not RecruitingScreeningMetastatic Melanoma / Metastatic Melanoma, BRAF V600 Mutation Positive1
2Active Not RecruitingTreatmentCancer, Breast1
2Active Not RecruitingTreatmentMicrosatellite Stable Colorectal Cancer / Microsatellite Unstable Colorectal Cancer / Mismatch Repair Deficient Colorectal Cancer / Mismatch Repair Proficient Colorectal Cancer / MSI Negative Colorectal Cancer / MSI Positive Colorectal Cancer1
2Active Not RecruitingTreatmentMelanoma1
2Not Yet RecruitingBasic ScienceMetastatic Colorectal Cancers1
2Not Yet RecruitingTreatmentCancer of the Ovary / Fallopian Tube Cancer / Primary Peritoneal Carcinoma1
2Not Yet RecruitingTreatmentMelanoma, Malignant, of Soft Parts1
2Not Yet RecruitingTreatmentMelanoma / Melanoma (Skin) / Melanoma Stage1
2Not Yet RecruitingTreatmentMetastatic Melanoma1
2RecruitingOtherCancer, Breast / Estrogen Receptor-Positive Breast Cancer1
2RecruitingTreatmentAdvanced Solid Tumors / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)1
2RecruitingTreatmentAppendiceal Adenocarcinoma / Cutaneous Squamous Cell Carcinoma / Malignant Neoplasms of Digestive Organs / Melanoma and Other Malignant Neoplasms of Skin / Small Bowel Adenocarcinoma1
2RecruitingTreatmentBRAF V600 mutation / Malignant Melanoma Stage IV / Metastatic Brain Tumors1
2RecruitingTreatmentBRAF V600E Mutation Present / Papillary Craniopharyngioma1
2RecruitingTreatmentCancer of Unknown Primary Site1
2RecruitingTreatmentCancers / Neoplasia / Neoplasms / Tumors1
2RecruitingTreatmentCarcinoma of Gallbladder / Intrahepatic Cholangiocarcinoma / Non-Resectable Cholangiocarcinoma / Recurrent Cholangiocarcinoma / Stage IV Intrahepatic Cholangiocarcinoma AJCC v8 / Unresectable Cholangiocarcinoma1
2RecruitingTreatmentClinical Stage III Cutaneous Melanoma AJCC v8 / Pathologic Stage III Cutaneous Melanoma AJCC v8 / Pathologic Stage IIIA Cutaneous Melanoma AJCC v8 / Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 / Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 / Pathologic Stage IIID Cutaneous Melanoma AJCC v81
2RecruitingTreatmentHistiocytic Disorders1
2RecruitingTreatmentKRAS Gene Mutation / Recurrent Non-Small Cell Lung Carcinoma / Stage IV Non-Small Cell Lung Cancer AJCC v71
2RecruitingTreatmentMalignant Melanoma2
2RecruitingTreatmentMalignant Neoplasm of Breast1
2RecruitingTreatmentMelanoma1
2RecruitingTreatmentNeoplasms1
2RecruitingTreatmentTumors, Solid1
2SuspendedTreatmentColorectal Cancers1
2TerminatedTreatmentActive Melanoma Brain Metastases1
2TerminatedTreatmentMelanoma1
2TerminatedTreatmentMelanoma / Metastatic Melanoma1
2WithdrawnTreatmentStage IIIB-C Melanoma1
3Active Not RecruitingTreatmentColorectal Cancers1
3Active Not RecruitingTreatmentMalignant Melanoma1
3RecruitingTreatmentAdvanced BRAFV600 Wild-type Melanoma1
3RecruitingTreatmentMelanoma1
3WithdrawnTreatmentMelanoma1
Not AvailableActive Not RecruitingNot AvailableMelanoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral20 mg
Tablet, film coatedOral20 mg/1mg
Tablet, film coatedOral20 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8362002No2006-10-052026-10-05Us
US7803839No2007-02-012027-02-01Us

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

Taxonomy

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
Aminobenzamide / Anthranilamide / Aminobenzoic acid or derivatives / 3-halobenzoic acid or derivatives / 2-aminobenzamide / 4-halobenzoic acid or derivatives / Halobenzoic acid or derivatives / Benzoyl / Aniline or substituted anilines / Iodobenzene
show 31 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not 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 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. [PubMed:26384788]

Enzymes

Kind
Protein
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 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. [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
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. [PubMed:25243894]

Transporters

Kind
Protein
Organism
Human
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. [PubMed:26384788]
Kind
Protein
Organism
Human
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 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. [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 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. [PubMed:25243894]

Drug created on October 21, 2007 16:24 / Updated on September 21, 2018 00:13