trametinib   Click here for help

GtoPdb Ligand ID: 6495

Synonyms: GSK1120212 | GSK1120212B | GSK212 | JTP 74057 | Mekinist® | trametinib dimethyl sulfoxide
Approved drug PDB Ligand
trametinib is an approved drug (FDA (2013), EMA (2014))
Compound class: Synthetic organic
Comment: Trametinib is a Type-3 kinase inhibitor. Marketed formulations contain trametinib dimethyl sulfoxide (PubChem CID 50992434).
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 6
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 106.61
Molecular weight 615.08
XLogP 6.37
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES CC(=O)Nc1cccc(c1)n1c(=O)n(C2CC2)c(=O)c2c1c(C)c(=O)n(c2Nc1ccc(cc1F)I)C
Isomeric SMILES CC(=O)Nc1cccc(c1)n1c(=O)n(C2CC2)c(=O)c2c1c(C)c(=O)n(c2Nc1ccc(cc1F)I)C
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)
InChI Key LIRYPHYGHXZJBZ-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
No information available.
Summary of Clinical Use Click here for help
Used to treat BRAF V600 mutation positive metastatic melanomas.
In April 2018, the FDA approved the use of dabrafenib in combination with trametinib for the adjuvant treatment of patients with BRAF V600E or V600K mutated melanoma (as detected by an FDA-approved test) and involvement of lymph node(s), following complete resection. Then in May, this same combination was approved (FDA) for the treatment of locally advanced/metastatic BRAF V600E +ve anaplastic thyroid cancer. The EMA issued orphan drug designation for the use of trametinib with dabrafenib in the treatment of low- and high-grade gliomas with a BRAF V600E mutations, in January 2024.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Trametinib inhibits MAP2K1 and MAP2K2 (aka MEK1 and 2) in the p42/p44 MAPK pathway, which is hyper-stimulated in cancers driven by constitutively active BRAF V600 mutations (eg in melanomas) and reduces cell growth in vitro and in vivo [1].
Pharmacokinetics Click here for help
Absorption/Distribution
Following oral administration (best administered in the fasted state), time to peak plasma concentration (Tmax) is 1.5 hours. Mean absolute bioavailability of a single 2mg oral dose of trametinib tablet is 72%. Trametinib is 97.4% bound to human plasma proteins.
Biotransformation/Metabolism
After repeat dosing, in excess of 75% of drug-related material in plasma is the parent compound. Metabolism is predominantly via deacetylation, probably mediated by hydrolytic enzymes such as carboxyl-esterases or amidases.
Elimination
Estimated elimination half-life is 3.9 to 4.8 days. Excretion of trametinib is primarily via the feces (>80%), with <20% recovered in the urine. The parent compound accounts for <0.1% of the recovered dose.
Population pharmacokinetics
There are no clinically relevant differences in exposure to trametinib associated with age, gender or race. Data to evaluate potential differences in the exposure of trametinib by race or ethnicity are lacking. No studies have been conducted to evaluate the pharmacokinetics of trametinib in pediatric patients.
Organ function impairment
Mild hepatic impairment has no clinically important effect on total exposure to trametinib. The pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment. Given the low level of renal excretion, renal impairment is unlikely to have a clinically relevant effect on total exposure to trametinib.
External links Click here for help
For extended ADME data see the following:

Electronic Medicines Compendium (eMC)
Drugs.com
European Medicines Agency (EMA)