NAV

Trametinib

Identification

Summary

Trametinib is a kinase inhibitor used alone or in combination with dabrafenib to treat patients with cancers with specific BRAF mutations, such as melanoma and non-small cell lung cancer.

Brand Names
Mekinist
Generic Name
Trametinib
DrugBank Accession Number
DB08911
Background

Trametinib is an orally bioavailable mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 inhibitor.4,3 It was first approved by the FDA in May 2013 for the treatment of melanoma.4 It was later approved by Health Canada on July 18, 2013 9 and by the European Commission on June 30, 2014.8 Trametinib is currently approved to treat a variety of cancers with BRAF mutations, such as non-small cell lung cancer and thyroid cancer, as monotherapy or in combination with dabrafenib, a BRAF inhibitor, for improved therapeutic efficacy. Originally developed by Japan Tobacco, trametinib was initially investigated for treating inflammation, but further studies for this indication were not pursued.4

Type
Small Molecule
Groups
Approved
Structure
3D
Similar Structures
Weight
Average: 615.3948
Monoisotopic: 615.077875874
Chemical Formula
C26H23FIN5O4
Synonyms
  • Tramétinib
  • Trametinib
  • Trametinibum
External IDs
  • GSK 1120212
  • GSK-1120212
  • GSK1120212
  • JTP 74057
  • JTP-74057
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Pharmacology

Indication

Trametinib is indicated as monotherapy for the treatment of BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations.6,8

It is used in combination with dabrafenib for the:

  • treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations.7
  • adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection.7,8
  • treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation.7 In Europe, it is indicated for the treatment of adults with advanced non-small cell lung cancer with a BRAF V600 mutation.8
  • treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options.7
  • the treatment of adult and pediatric patients six years of age and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. In the US, this indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).7
  • the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.7

In the US, BRAF V600E or V600K mutations must be detected by an FDA-approved test. Trametinib is not indicated for the treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition.7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatAdvanced non-small cell lung cancer (nsclc)Regimen in combination with: Dabrafenib (DB08912)•••••••••••••••••
Used in combination to treatLow-grade gliomaRegimen in combination with: Dabrafenib (DB08912)••••••••••••••••••• •••••••• •••••••
Used as adjunct in combination to treatMelanomaRegimen in combination with: Dabrafenib (DB08912)••••••••••••••••• •••• •••••••••••• •••••••• •••••••• •••••••••
Used as adjunct in combination to treatMelanomaRegimen in combination with: Dabrafenib (DB08912)••••••••••••••••• •••• •••••••••••• •••••••• •••••••• •••••••••
Used in combination to treatMetastatic anaplastic thyroid cancerRegimen in combination with: Dabrafenib (DB08912)•••••••••••••••••••••• ••••••••••• ••••••••• •••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumours in vitro and in vivo. Trametinib is often used in combination with dabrafenib, a BRAF inhibitor. In BRAF-mutant colorectal cancer, induction of EGFR-mediated MAPK pathway re-activation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors.7

Mechanism of action

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) pathway, also known as the RAS-RAF-MEK-ERK pathway, activates a cascade of cell surface receptors and intracellular downstream signalling molecules. Activated RAS protein activates RAF, a serine/threonine kinase that activates other downstream proteins 1,5 such as mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEKs then activates ERK, which works on several target proteins and nuclear transcription factors that regulate cell proliferation, differentiation, survival, and growth.1,5 ARAF, BRAF, and CRAF are three isoforms of RAF identified in humans. In particular, BRAF is known to be the most critical activator in melanoma.1,5 Certain cancers, such as melanoma, are associated with BRAF mutations, with one study suggesting that BRAF is mutated in about 50% of melanoma tumours.5 BRAF V600E and V600K mutations account for 95% of BRAF mutations.4 These BRAF mutations cause constitutive activation of the RAS-RAF-MEK-ERK pathway,7,8 leading to dysregulated proliferation and survival of tumour cells.4

Trametinib is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2.7,8 By binding to unphosphorylated MEK1 and MEK2 with high affinity, trametinib blocks the catalytic activity of MEKs.1,2,4 It also maintains MEK in an unphosphorylated form, preventing phosphorylation and activation of MEKs.1,2,4

In vitro studies suggest that dual inhibition of the MAPK pathway by MEK and B-RAF inhibitors is associated with a synergistic effect and improved therapeutic efficacy in cancers compared to using either drug alone.5 The combined use of trametinib and dabrafenib, a BRAF inhibitor, results in more significant growth inhibition of BRAF V600 mutation-positive tumour cell lines in vitro and prolonged inhibition of tumour growth in BRAF V600 mutation-positive tumour xenografts compared to either drug alone.7 The combined inhibition of MEK by trametinib and RAF by dabrafenib delays the emergence of resistance in vivo in BRAF V600 mutation-positive melanoma xenografts.8

TargetActionsOrganism
ADual specificity mitogen-activated protein kinase kinase 1
inhibitor
Humans
ADual specificity mitogen-activated protein kinase kinase 2
inhibitor
Humans
Absorption

Following oral administration, trametinib is rapidly and readily absorbed.5 The absorption was examined in patients with solid tumours and BRAF V600 mutation-positive metastatic melanoma. Following the administration of trametinib tablets 0.125 mg (0.0625 times the approved recommended adult dosage) to 4 mg (2 times the approved recommended adult dosage) daily, both Cmax and AUC increased dose-proportionally. Intersubject variability in AUC and Cmax at steady state is 22% and 28%, respectively.7 Trametinib accumulates with daily repeat dosing with a mean accumulation ratio of 6.0 at 2 mg once daily dose. Steady-state was achieved by Day 15.8

The mean absolute bioavailability of trametinib is 72% for oral tablets and 81% for oral solution. The Tmax is 1.5 hours. A high-fat, high-calorie meal (approximately 1000 calories) decreased trametinib AUC by 24% and Cmax by 70%, and delayed Tmax by approximately four hours as compared with fasted conditions.7

Volume of distribution

The apparent volume of distribution (Vc/F) is 214 L.7

Protein binding

Trametinib is 97.4% bound to human plasma proteins.7

Metabolism

Trametinib predominantly undergoes deacetylation mediated by carboxylesterases (i.e., carboxylesterase 1b/c and 2) and other hydrolytic enzymes. The deacetylated metabolite may further be glucuronidated.8 In vitro findings suggest that deacetylation may also be accompanied by mono-oxygenation,7 hydroxylation, and glucuronidation.5 CYP3A4-mediated oxidation is a minor pathway.8 Four metabolites (M1/2/3/4) have been characterized in patients with advanced cancers. In vitro, the M1 and M3 metabolites demonstrated approximately equal or 10-fold less potent phospho-MEK1-inhibiting activity than the parent compound.5

Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity represented the parent compound. According to findings from metabolite profiling after repeat dosing of trametinib, unchanged parent drug accounted for greater than or equal to 75% of drug-related material in plasma.7

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Route of elimination

Following oral administration of [14C]-trametinib, greater than 80% of excreted radioactivity was recovered in the feces while less than 20% of excreted radioactivity was recovered in the urine with less than 0.1% of the excreted dose as the parent molecule.7

Half-life

The estimated elimination half-life is 3.9 to 4.8 days.7

Clearance

The apparent clearance is 4.9 L/h.7

Adverse Effects
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Toxicity

There is no information regarding the acute toxicity (LD50) of trametinib. The highest doses of trametinib evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on two consecutive days, followed by 3 mg once daily. Out of seven patients treated on one of these two schedules, two patients experienced retinal pigment epithelial detachments.7 In clinical trials with trametinib monotherapy, one case of accidental overdose was reported from a single dose of 4 mg: no adverse events were reported in this event.8 Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of drug overdose.7

Pathways
Not Available
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Not Available

Interactions

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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
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interactions in your software
AbacavirAbacavir may decrease the excretion rate of Trametinib which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Trametinib which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Trametinib which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Trametinib which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Trametinib which could result in a lower serum level and potentially a reduction in efficacy.
Food Interactions
  • Take separate from meals. Take at least 1 hour before or at least 2 hours after a meal. A high-fat, high-calorie meal decreases trametinib AUC and Cmax, and delays Tmax.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Trametinib dimethyl sulfoxideBSB9VJ5TUT1187431-43-1OQUFJVRYDFIQBW-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MekinistTablet, film coated1 mg/1OralGlaxoSmithKline LLC2013-06-172013-05-29US flag
MekinistTablet, film coated2 mgOralNovartis Europharm Limited2016-10-06Not applicableEU flag
MekinistTablet, film coated0.5 mg/1OralGlaxoSmithKline Manufacturing SpA2013-06-17Not applicableUS flag
MekinistTablet, film coated0.5 mgOralNovartis Europharm Limited2016-10-06Not applicableEU flag
MekinistTablet, film coated0.5 mgOralNovartis Europharm Limited2016-09-08Not applicableEU flag

Categories

ATC Codes
L01EE01 — Trametinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyridopyrimidines. These are compounds containing a pyridopyrimidine, which consists of a pyridine fused to a pyrimidine. Pyridine is 6-membered ring consisting of five carbon atoms and a nitrogen atom. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridopyrimidines
Sub Class
Not Available
Direct Parent
Pyridopyrimidines
Alternative Parents
Acetanilides / N-acetylarylamines / Aniline and substituted anilines / Aminopyridines and derivatives / Pyrimidones / Pyridinones / Fluorobenzenes / Methylpyridines / Iodobenzenes / Aryl fluorides
show 16 more
Substituents
Acetamide / Acetanilide / Amine / Amino acid or derivatives / Aminopyridine / Anilide / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide
show 34 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, organoiodine compound, acetamides, aromatic amine, cyclopropanes, ring assembly, pyridopyrimidine (CHEBI:75998)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
33E86K87QN
CAS number
871700-17-3
InChI Key
LIRYPHYGHXZJBZ-UHFFFAOYSA-N
InChI
InChI=1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)
IUPAC Name
N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-d]pyrimidin-1-yl}phenyl)acetamide
SMILES
CN1C(=O)C(C)=C2N(C(=O)N(C3CC3)C(=O)C2=C1NC1=CC=C(I)C=C1F)C1=CC(NC(C)=O)=CC=C1

References

General References
  1. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. [Article]
  2. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, Cox DS, Xu Y, Morris SR, Peddareddigari VG, Le NT, Hart L, Bendell JC, Eckhardt G, Kurzrock R, Flaherty K, Burris HA 3rd, Messersmith WA: Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012 Aug;13(8):773-81. doi: 10.1016/S1470-2045(12)70270-X. Epub 2012 Jul 16. [Article]
  3. Zeiser R: Trametinib. Recent Results Cancer Res. 2014;201:241-8. doi: 10.1007/978-3-642-54490-3_15. [Article]
  4. Wright CJ, McCormack PL: Trametinib: first global approval. Drugs. 2013 Jul;73(11):1245-54. doi: 10.1007/s40265-013-0096-1. [Article]
  5. Ho MY, Morris MJ, Pirhalla JL, Bauman JW, Pendry CB, Orford KW, Morrison RA, Cox DS: Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers. Xenobiotica. 2014 Apr;44(4):352-68. doi: 10.3109/00498254.2013.831143. Epub 2013 Aug 23. [Article]
  6. FDA Approved Drug Products: MEKINIST (trametinib) tablets, for oral use [Link]
  7. FDA Approved Drug Products: MEKINIST (trametinib) tablets or solution, for oral use (March 2023) [Link]
  8. EMA Approved Drug Products: Mekinist (trametinib) Oral Tablets [Link]
  9. Health Canada Approved Drug Products: MEKINIST (Trametinib) Oral Tablets [Link]
  10. FDA Approved Drug Products: MEKINIST (trametinib) tablets or solution, for oral use (June 2023) [Link]
KEGG Drug
D10175
PubChem Compound
11707110
PubChem Substance
175427149
ChemSpider
9881833
BindingDB
50531540
RxNav
1425099
ChEBI
75998
ChEMBL
CHEMBL2103875
ZINC
ZINC000043100709
PharmGKB
PA166115364
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trametinib

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentAnaplastic Astrocytoma (AA) / Anaplastic Ganglioglioma / Anaplastic Oligodendroglioma (AO) / Angiocentric glioma / Astrocytoma / Central Neurocytoma / Cerebellar Liponeurocytoma / Chordoid Glioma of Third Ventricle / Desmoplastic Infantile Astrocytoma and Ganglioglioma / Diffuse Astrocytoma / Dysplastic Gangliocytoma of Cerebrellum / Extraventricular Neurocytoma / Gangliocytoma / Ganglioglioma / Giant Cell Astrocytoma / High Grade Glioma: Glioblastoma (GBM) / Neurofibromatosis, type 1 (von Recklinghausen's disease) / Oligodendroglioma, Childhood / Papillary Glioneuronal Tumor / Pilocytic Astrocytoma / Pleomorphic Xanthoastrocytoma / Pleomorphic Xanthoastrocytoma, Anaplastic / Rosette-forming Glioneurona Tumor1
4RecruitingTreatmentHigh Grade Glioma (HGG) / Melanoma / Non-Small Cell Lung Cancer (NSCLC) / Rare Cancers / Solid Tumors1
3Active Not RecruitingTreatmentClinical Stage III Cutaneous Melanoma AJCC v8 / Clinical Stage IV Cutaneous Melanoma AJCC v8 / Metastatic Melanoma / Recurrent Melanoma / Unresectable Melanoma1
3Active Not RecruitingTreatmentMelanoma1
3CompletedTreatmentMalignant Melanoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder, for solutionOral0.05 mg/1mL
Powder, for solutionOral4.7 mg
TabletOral0.5 mg
TabletOral1 mg
TabletOral2 mg
Tablet, film coatedOral.5 mg/1
Tablet, film coatedOral0.5 mg/1
Tablet, film coatedOral1 mg/1
Tablet, film coatedOral1 MG
Tablet, film coatedOral2 mg/1
Tablet, film coatedOral0.5 mg
Tablet, coatedOral2 mg
Tablet, film coatedOral2 mg
Tablet, coatedOral0.5 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8703781Yes2014-04-222031-04-15US flag
US8835443Yes2014-09-162025-12-10US flag
US9271941Yes2016-03-012032-07-28US flag
US9155706Yes2015-10-132032-07-28US flag
US7378423Yes2008-05-272027-11-29US flag
US8580304Yes2013-11-122032-07-28US flag
US8952018Yes2015-02-102031-04-15US flag
US9399021Yes2016-07-262032-07-28US flag
US10869869Yes2020-12-222034-03-02US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<1 mg/mLhttps://www.selleckchem.com/msds/MSDS_S2673.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0307 mg/mLALOGPS
logP3.45ALOGPS
logP3.18Chemaxon
logS-4.3ALOGPS
pKa (Strongest Acidic)12.6Chemaxon
pKa (Strongest Basic)-3.2Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area102.06 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity156.38 m3·mol-1Chemaxon
Polarizability55.07 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9733
Blood Brain Barrier+0.8217
Caco-2 permeable-0.5193
P-glycoprotein substrateNon-substrate0.5945
P-glycoprotein inhibitor INon-inhibitor0.6449
P-glycoprotein inhibitor IINon-inhibitor0.8622
Renal organic cation transporterNon-inhibitor0.899
CYP450 2C9 substrateNon-substrate0.7215
CYP450 2D6 substrateNon-substrate0.8232
CYP450 3A4 substrateSubstrate0.5735
CYP450 1A2 substrateNon-inhibitor0.8599
CYP450 2C9 inhibitorNon-inhibitor0.5775
CYP450 2D6 inhibitorNon-inhibitor0.9521
CYP450 2C19 inhibitorNon-inhibitor0.8769
CYP450 3A4 inhibitorNon-inhibitor0.836
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9337
Ames testAMES toxic0.5498
CarcinogenicityNon-carcinogens0.8078
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.3412 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9539
hERG inhibition (predictor II)Non-inhibitor0.6602
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0000019000-844224305ad93f28de2f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0000069000-323378cf7e4c3388e64d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0000029000-a470b9a80582c9abed56
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0kur-0000192000-1965a4ac3001eec1be3a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-03g0-1300094000-fc69d3b7860a366cd804
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0900000000-ac2bb30239ab5b4823f8
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-216.78743
predicted
DeepCCS 1.0 (2019)
[M+H]+219.183
predicted
DeepCCS 1.0 (2019)
[M+Na]+225.0955
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Details1. Dual specificity mitogen-activated protein kinase kinase 1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
The IC50 values for the unphosphorylated and phosphorylated forms of MEK1 are 0.7 nM and 13.2 nM, respectively.
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. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. [Article]
  2. Ho MY, Morris MJ, Pirhalla JL, Bauman JW, Pendry CB, Orford KW, Morrison RA, Cox DS: Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers. Xenobiotica. 2014 Apr;44(4):352-68. doi: 10.3109/00498254.2013.831143. Epub 2013 Aug 23. [Article]
  3. FDA Approved Drug Products: MEKINIST (trametinib) tablets or solution, for oral use (March 2023) [Link]
  4. Health Canada Approved Drug Products: MEKINIST (Trametinib) Oral Tablets [Link]
Details2. Dual specificity mitogen-activated protein kinase kinase 2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
The IC50 values for the unphosphorylated and phosphorylated forms of MEK2 are 0.9 nM and 10.7 nM, respectively.
General Function
Scaffold protein binding
Specific Function
Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).
Gene Name
MAP2K2
Uniprot ID
P36507
Uniprot Name
Dual specificity mitogen-activated protein kinase kinase 2
Molecular Weight
44423.735 Da
References
  1. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. [Article]
  2. FDA Approved Drug Products: MEKINIST (trametinib) tablets or solution, for oral use (March 2023) [Link]
  3. Health Canada Approved Drug Products: MEKINIST (Trametinib) Oral Tablets [Link]

Enzymes

Details1. Cytochrome P450 2C8
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Trametinib is an inhibitor of CYP2C8 in vitro.
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Thota R, Johnson DB, Sosman JA: Trametinib in the treatment of melanoma. Expert Opin Biol Ther. 2015 May;15(5):735-47. doi: 10.1517/14712598.2015.1026323. Epub 2015 Mar 26. [Article]
  2. FDA Approved Drug Products: MEKINIST (trametinib) tablets, for oral use [Link]
Details2. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
Curator comments
Trametinib is an inducer of CYP3A in vitro.
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. Lugowska I, Kosela-Paterczyk H, Kozak K, Rutkowski P: Trametinib: a MEK inhibitor for management of metastatic melanoma. Onco Targets Ther. 2015 Aug 25;8:2251-9. doi: 10.2147/OTT.S72951. eCollection 2015. [Article]
  2. FDA Approved Drug Products: MEKINIST (trametinib) tablets, for oral use [Link]
  3. EMA Approved Drug Products: Mekinist (trametinib) Oral Tablets [Link]

Drug created at June 24, 2013 21:36 / Updated at October 04, 2023 10:01