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

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By Bissan Al-Lazikani



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.
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Comments

Vladimir Chupakhin said…
whoa! this tautomeric form looks weird!
21 June 2013 at 21:40
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.....
22 June 2013 at 08:00
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