TRAMETINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C26H23FIN5O4
Molecular Weight	615.3948
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CN1C(=O)C(C)=C2N(C(=O)N(C3CC3)C(=O)C2=C1NC4=CC=C(I)C=C4F)C5=CC(NC(C)=O)=CC=C5

InChI

InChIKey=LIRYPHYGHXZJBZ-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C26H23FIN5O4
Molecular Weight	615.3948
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Trametinib is a reversible and specific inhibitor of mitogen-activated protein kinase kinases MEK1 and MEK2 which are involved in a RAS/RAF/MEK/ERK signaling pathway and control cell growth, survival, and differentiation. By inhibiting MEK1 and MEK2 trametinib blocks dual phosphorylation of ERK1/2 and stops cell cycling. In addition, trametinib blocks BRAF pathway in the cells with BRAF V600E mutations. Trametinib (as a single agent and in combination with dabrafenib) is approved for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dual specificity mitogen-activated protein kinase kinase 1 20	Antagonist 2,778		0.9 nM [IC50]
Dual specificity mitogen-activated protein kinase kinase 2 9	Antagonist 2,778		1.8 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Melanoma 88	Primary		Approved 8,429	MEKINIST

C_max

Value	Dose	Co-administered	Analyte	Population
9.5 ng/mL	2 mg single, oral		TRAMETINIB plasma	Homo sapiens
8.03 ng/mL	2 mg single, oral		TRAMETINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
498 ng × h/mL	2 mg single, oral		TRAMETINIB plasma	Homo sapiens
525 ng × h/mL	2 mg single, oral		TRAMETINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
127 h	2 mg single, oral		TRAMETINIB plasma	Homo sapiens
264 h	2 mg single, oral		TRAMETINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
5%	2 mg single, oral		TRAMETINIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
2 mg 2 times / day multiple, oral	unhealthy, median age 54.5 years n = 211	Disc. AE: Left ventricular dysfunction, Cardiac failure...
2 mg 2 times / day multiple, oral	unhealthy, median age 54.5 years n = 211	Disc. AE: Rash, Diarrhea... Other AEs: Hypertension, Rash...
2 mg 1 times / day multiple, oral Recommended	unhealthy, median age 55 years n = 211	Other AEs: Skin rash, Skin rash...
2 mg 1 times / day multiple, oral Recommended	unhealthy, median age 55 years n = 211	Other AEs: Detachment of retinal pigment epithelium, Retinal vein occlusion...
2 mg 1 times / day multiple, oral Recommended	unhealthy, median age 55 years n = 211	Other AEs: Cardiomyopathy...

Showing 1 to 5 of 12 entries

Previous1 2 3Next

AEs

Show entries

AE	Significance	Dose	Population
ALT increased	0.5% Disc. AE	2 mg 2 times / day multiple, oral	unhealthy, median age 54.5 years n = 211
Abdominal pain upper	0.5% Disc. AE	2 mg 2 times / day multiple, oral	unhealthy, median age 54.5 years n = 211
Anemia	0.5% Disc. AE	2 mg 2 times / day multiple, oral	unhealthy, median age 54.5 years n = 211
Bilirubin increased	0.5% Disc. AE	2 mg 2 times / day multiple, oral	unhealthy, median age 54.5 years n = 211
CPK increased	0.5% Disc. AE	2 mg 2 times / day multiple, oral	unhealthy, median age 54.5 years n = 211

Showing 1 to 5 of 171 entries

Previous1 2 3 4 5…35Next

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1,737 inhibitor 1,587	substrate 1,037 inhibitor 1,767	substrate 1,217 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 911 P-gp 1,461 BCRP 699 OATP1B1 788 OATP1B3 706 CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C19 1,478	CYP1A2 1,054 CYP2C8 693 CYP2C19 991 P-gp 1,537 BCRP 561

Drug as perpetrator

Show entries

Target	Modality	Activity
CYP1A2 1,692	inhibitor 3,277	no
CYP2A6 739	inhibitor 3,277	no
CYP2B6 1,001	inhibitor 3,277	no
CYP2D6 1,891	inhibitor 3,277	no
CYP3A4 1,925	inhibitor 3,277	no

Showing 1 to 5 of 13 entries

Previous1 2 3Next

Drug as victim

Show entries

Target	Modality	Activity
BCRP 561	substrate 3,367	no
CYP1A2 1,054	substrate 3,367	no
CYP2C19 991	substrate 3,367	no
CYP2C8 693	substrate 3,367	no
CYP2C9 1,037	substrate 3,367	no

Showing 1 to 5 of 8 entries

Previous1 2Next

Tox targets

Show entries

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

Showing 1 to 1 of 1 entries

Previous1Next

Sourcing

Sourcing

Show entries

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:75998	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:75998
ChemicalBook	CB32514557	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32514557
MolPort	MolPort-019-879-136	https://www.molport.com/shop/molecule-link/MolPort-019-879-136
Selleck Chemicals	gsk1120212-(jtp-74057)	http://www.selleckchem.com/products/gsk1120212-(jtp-74057).html
ZINC	ZINC000043100709	http://zinc15.docking.org/substances/ZINC000043100709

Showing 1 to 5 of 6 entries

Previous1 2Next

PubMed

Show entries

Title	Date	PubMed
Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo.	2011 Jul	21523318
GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition.	2011 Mar 1	21245089

Showing 1 to 2 of 2 entries

Previous1Next

Patents

Sample Use Guides

In Vivo Use Guide

Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST. The recommended dosage regimens of MEKINIST are 2 mg orally once daily as a single agent or in combination with dabrafenib 150 mg orally twice daily.Take MEKINIST at least 1 hour before or at least 2 hours after a meal.

Route of Administration: Oral

In Vitro Use Guide

A375 and SK-MEL-28 untransfected or transfected with Mcl-1 plasmid were treated with 2 nM trametinib for 72 hours. The cell survival was evaluated by sulforhodamine B assay.