Skip to main content

New Drug Approvals 2013 - Pt. X - Trametinib (Mekinist®)




ATC code:L01XE15
Wikipedia:Trametinib
ChEMBL2103875

On May 29th 2013, the FDA approved trametinib (Mekinist®) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, and who have not received prior BRAF inhibitor treatment. Trametinib inhibits mutant BRAF signalling through the inhibition of a downstream kinase, MEK. In clinical trials trametinib improved the progression-free survival (PFS) from 1.5 months on standard of care chemotherapy to 4.8 months on trametinib.

Trametinib is the first approved targeted MEK inhibitor. It inhibits the kinase catalytic activity of its targets, mitogen-activated extracellular signal regulated kinase 1 and 2 ( MAP2K1 AKA MEK1, Uniprot:Q02750) and MAP2K2 AKA MEK2, Uniprot:P36507).


The sequences of the targets are here:

>sp|Q02750|MP2K1_HUMAN Dual specificity mitogen-activated protein kinase kinase 1 OS=Homo sapiens GN=MAP2K1 PE=1 SV=2
MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKV
GELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHE
CNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYL
REKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHY
SVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSY
GMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF
IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV

>sp|P36507|MP2K2_HUMAN Dual specificity mitogen-activated protein kinase kinase 2 OS=Homo sapiens GN=MAP2K2 PE=1 SV=1
MLARRKPVLPALTINPTIAEGPSPTSEGASEANLVDLQKKLEELELDEQQKKRLEAFLTQ
KAKVGELKDDDFERISELGAGNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQ
VLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEILGKVSIAVLRG
LAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQ
GTHYSVQSDIWSMGLSLVELAVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRP
PGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCLIKNPAERADL
KMLTNHTFIKRSEVEEVDFAGWLCKTLRLNQPGTPTRTAV

Trametinib is administered as tablets containing trametinib dimethyl sulfoxide, the molecular formula C26H23FIN5O4 . C2H6OS with a molecular mass of 693.53. The molecular weight of trametinib itself is 615.4 and its AlogP is 3.18. Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L. Tmax occurs 1.5 hours after dosing, and mean oral bioavailavility is 72%. Trametinib is primarily metabolised by deamidation and subsequent clearance with a half life of 3.9 to 4.8 days, clearance is 4.9 L/hr. Trametinib is not an inhibitor or substrate for CYP or PGP systems, but is an inducer of CYP3A4 activity.

Standard dose is 2mg once daily, with lower doses recommended if side effects are observed. Significant, use limiting side effects are seen in many patients.

Mekinist is produced by GSK

The Prescribing Information is here.

Comments

whoa! this tautomeric form looks weird!
jpo said…
Yes, it was, all fixed now though - should have used ChEMBL in the first place. The unusual tatuomer came from a toolkit conversion from InChI to mol.....

Popular posts from this blog

ChEMBL 34 is out!

We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains:         2,431,025 compounds (of which 2,409,270 have mol files)         3,106,257 compound records (non-unique compounds)         20,772,701 activities         1,644,390 assays         15,598 targets         89,892 documents Data can be downloaded from the ChEMBL FTP site:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding vaccines). 71 out of the 882 newly added EMA drugs are only authorised by EMA, rather than from other regulatory bodies e.g.

New SureChEMBL announcement

(Generated with DALL-E 3 ∙ 30 October 2023 at 1:48 pm) We have some very exciting news to report: the new SureChEMBL is now available! Hooray! What is SureChEMBL, you may ask. Good question! In our portfolio of chemical biology services, alongside our established database of bioactivity data for drug-like molecules ChEMBL , our dictionary of annotated small molecule entities ChEBI , and our compound cross-referencing system UniChem , we also deliver a database of annotated patents! Almost 10 years ago , EMBL-EBI acquired the SureChem system of chemically annotated patents and made this freely accessible in the public domain as SureChEMBL. Since then, our team has continued to maintain and deliver SureChEMBL. However, this has become increasingly challenging due to the complexities of the underlying codebase. We were awarded a Wellcome Trust grant in 2021 to completely overhaul SureChEMBL, with a new UI, backend infrastructure, and new f

Accessing SureChEMBL data in bulk

It is the peak of the summer (at least in this hemisphere) and many of our readers/users will be on holiday, perhaps on an island enjoying the sea. Luckily, for the rest of us there is still the 'sea' of SureChEMBL data that awaits to be enjoyed and explored for hidden 'treasures' (let me know if I pushed this analogy too far). See here and  here for a reminder of SureChEMBL is and what it does.  This wealth of (big) data can be accessed via the SureChEMBL interface , where users can submit quite sophisticated and granular queries by combining: i) Lucene fields against full-text and bibliographic metadata and ii) advanced structure query features against the annotated compound corpus. Examples of such queries will be the topic of a future post. Once the search results are back, users can browse through and export the chemistry from the patent(s) of interest. In addition to this functionality, we've been receiving user requests for  local (behind the