Identification

Name
Trametinib
Accession Number
DB08911
Type
Small Molecule
Groups
Approved
Description

Trametinib dimethyl sulfoxide is a kinase inhibitor. Each 1-mg tablet contains 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. FDA approved on May 29, 2013.

Structure
Thumb
Synonyms
  • GSK 1120212
  • Trametinib Dimethyl Sulfoxide
  • Trametinibum
External IDs
GSK1120212 / JTP 74057 / JTP-74057
Product Ingredients
IngredientUNIICASInChI Key
Trametinib dimethyl sulfoxideBSB9VJ5TUT1187431-43-1OQUFJVRYDFIQBW-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MekinistTablet, film coated0.5 mgOralNovartis Europharm Limited2014-06-30Not applicableEu
MekinistTablet, film coated.5 mg/1OralGlaxosmithkline Inc2013-06-172016-12-31Us
MekinistTablet, film coated2 mgOralNovartis Europharm Limited2014-06-30Not applicableEu
MekinistTablet, film coated2 mgOralNovartis Europharm Limited2014-06-30Not applicableEu
MekinistTablet, film coated2 mg/1OralNovartis2016-03-17Not applicableUs
MekinistTablet, film coated2 mg/1OralGlaxosmithkline Inc2013-06-172016-12-31Us
MekinistTablet, film coated0.5 mgOralNovartis Europharm Limited2014-06-30Not applicableEu
MekinistTablet, film coated2 mgOralNovartis Europharm Limited2014-06-30Not applicableEu
MekinistTablet, film coated0.5 mgOralNovartis Europharm Limited2014-06-30Not applicableEu
MekinistTablet1 mgOralNovartisNot applicableNot applicableCanada
Categories
UNII
33E86K87QN
CAS number
871700-17-3
Weight
Average: 615.3948
Monoisotopic: 615.077875874
Chemical Formula
C26H23FIN5O4
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

Pharmacology

Indication

Trametinib is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.

Structured Indications
Pharmacodynamics

When 1 mg and 2 mg trametinib is given to patients with BRAF V600 mutation-positive melanoma, an inhibition of phosphorylated ERK and Ki67, and an increase in p27 was observed. These changes indicate that trametinib caused a decrease in cell proliferation and an increase in apoptosis, respectively.

Mechanism of action

Trametinib is a reversible, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Trametinib helps with melanoma with the BRAF V600E or V600K as the mutation results in the constitutive activation of the BRAF pathway which includes MEK1 and MEK2.

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

Trametinib is rapidly absorbed. When an oral administration of trametinib was given to patients with BRAF V600 mutation-positive melanoma, peak plasma concentration occurred 1.5 hours post-dose (Tmax). A single 2 mg oral dose has a bioavailability of 72%. When a dose of 2mg/day is given, the peak plasma concentration (Cmax) is 22.2 ng/mL.

Volume of distribution

Apparent volume of distribution (Vd/F) = 214 L

Protein binding

97.4% bound to human plasma proteins.

Metabolism

Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. The cytochrome P450 enzyme system is not involved with the metabolism of trametinib. The predominant circulating component in the plasma is the parent compound.

Route of elimination

80% of the dose is excreted in the feces. <20% of the dose is excreted in the urine with <0.1% of the excreted dose in the form of the parent compound.

Half life

Elimination half-life = 3.9-4.8 days.

Clearance

Apparent clearance = 4.9 L/h.

Toxicity

Most common adverse reactions (≥20%) for trametinib include rash, diarrhea, and lymphedema.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Trametinib.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Trametinib.Experimental
AmodiaquineThe serum concentration of Amodiaquine can be increased when it is combined with Trametinib.Approved, Investigational
AripiprazoleThe serum concentration of Aripiprazole can be decreased when it is combined with Trametinib.Approved, Investigational
BevacizumabBevacizumab may increase the cardiotoxic activities of Trametinib.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Trametinib.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Trametinib.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Trametinib.Experimental
DabrafenibThe risk or severity of adverse effects can be increased when Trametinib is combined with Dabrafenib.Approved
DeslanosideDeslanoside may decrease the cardiotoxic activities of Trametinib.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Trametinib.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Trametinib.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Trametinib.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Trametinib.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Trametinib.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Trametinib.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Trametinib.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Trametinib.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Trametinib.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Trametinib.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Trametinib.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Trametinib.Experimental
SaxagliptinThe serum concentration of Saxagliptin can be decreased when it is combined with Trametinib.Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Trametinib.Approved, Investigational
Food Interactions
  • When taken with a high-fat, high-calorie meal, AUC and Cmax decreased. Tmax was also prolonged compared to fasted conditions.

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. [PubMed:23432625]
External Links
KEGG Drug
D10175
PubChem Compound
11707110
PubChem Substance
175427149
ChemSpider
9881833
ChEBI
75998
ChEMBL
CHEMBL2103875
PharmGKB
PA166115364
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trametinib
ATC Codes
L01XE25 — Trametinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (517 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic ScienceCancer, Breast1
0RecruitingTreatmentAnaplastic Thyroid Cancers1
1Active Not RecruitingOtherCholangiocarcinomas / Soft-Tissue Sarcoma / Thyroid Cancers / Tumors, Solid1
1Active Not RecruitingTreatmentEndometrial Adenocarcinomas / Endometrial Clear Cell Adenocarcinoma / Endometrial Mixed Adenocarcinoma / Endometrial Serous Adenocarcinoma / Endometrial Undifferentiated Carcinoma / Recurrent Uterine Corpus Carcinoma1
1Active Not RecruitingTreatmentMetastatic Malignant Neoplasm in the Brain1
1Active Not RecruitingTreatmentRecurrent Rectal Cancer / Stage IIA Rectal Cancer / Stage IIB Rectal Cancer / Stage IIC Rectal Cancer / Stage IIIA Rectal Cancer / Stage IIIB Rectal Cancer / Stage IIIC Rectal Cancer1
1CompletedBasic ScienceCancers1
1CompletedOtherCancers2
1CompletedTreatmentAdvanced Malignancy / Cancers / Leukemia Acute Myeloid Leukemia (AML) / Oncology / Oncology Patients1
1CompletedTreatmentAdvanced and Selected Solid Tumors1
1CompletedTreatmentCancers7
1CompletedTreatmentCancers / Tumors, Solid1
1CompletedTreatmentLeukemia, Myelocytic, Acute / Tumors, Solid1
1CompletedTreatmentTumors, Solid3
1Not Yet RecruitingTreatmentBRAF Gene Mutation / Melanoma1
1Not Yet RecruitingTreatmentEGFR-mutant Non-small Cell Lung Cancer1
1Not Yet RecruitingTreatmentKRAS Gene Mutation / Metastatic Non-Squamous Non-Small Cell Lung Carcinoma / Recurrent Non-Squamous Non-Small Cell Lung Carcinoma / Stage IV Non-Small Cell Lung Cancer AJCC v71
1Not Yet RecruitingTreatmentRAS Family Gene Mutation / Stage III Colon Cancer AJCC v7 / Stage III Colorectal Cancer AJCC v7 / Stage III Rectal Cancer AJCC v7 / Stage IIIA Colon Cancer AJCC v7 / Stage IIIA Colorectal Cancer AJCC v7 / Stage IIIA Rectal Cancer AJCC v7 / Stage IIIB Colon Cancer AJCC v7 / Stage IIIB Colorectal Cancer AJCC v7 / Stage IIIB Rectal Cancer AJCC v7 / Stage IIIC Colon Cancer AJCC v7 / Stage IIIC Colorectal Cancer AJCC v7 / Stage IIIC Rectal Cancer AJCC v7 / Stage IV Colon Cancer AJCC v7 / Stage IV Colorectal Cancer AJCC v7 / Stage IV Rectal Cancer AJCC v7 / Stage IVA Colon Cancer AJCC v7 / Stage IVA Colorectal Cancer AJCC v7 / Stage IVA Rectal Cancer AJCC v7 / Stage IVB Colon Cancer AJCC v7 / Stage IVB Colorectal Cancer AJCC v7 / Stage IVB Rectal Cancer AJCC v71
1RecruitingTreatmentAdvanced Malignant Solid Neoplasm / Hepatic Complications / Metastatic Malignant Neoplasm in the Liver / Metastatic Malignant Solid Neoplasm / Metastatic Solid Neoplasm / Neoplasms, Advanced Solid / Solid Neoplasms / Unresectable Solid Neoplasm1
1RecruitingTreatmentBRAF V600E Mutation Present / BRAF V600K Mutation Present / Metastatic Malignant Solid Neoplasm / Metastatic Melanoma / Metastatic Solid Neoplasm / Recurrent Malignant Solid Neoplasm / Recurrent Melanoma / Recurrent Solid Neoplasm / Solid Neoplasms / Stage III Cutaneous Melanoma AJCC v7 / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIA Skin Melanoma / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIB Skin Melanoma / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IIIC Skin Melanoma / Stage IV Cutaneous Melanoma AJCC v6 and v7 / Stage IV Skin Melanoma / Stages III Skin Melanoma / Unresectable Solid Neoplasm1
1RecruitingTreatmentBRAF V600E Mutation Present / BRAF V600K Mutation Present / Metastatic Melanoma / Stage III Cutaneous Melanoma AJCC v7 / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIA Skin Melanoma / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIB Skin Melanoma / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IIIC Skin Melanoma / Stage IV Cutaneous Melanoma AJCC v6 and v7 / Stage IV Skin Melanoma / Stages III Skin Melanoma1
1RecruitingTreatmentCancers2
1RecruitingTreatmentCancers / Neuroblastomas1
1RecruitingTreatmentColorectal Cancer, Triple Negative Breast Cancer, NSCLC - Adenocarcinoma / Colorectal Cancers / Non-small Cell Lung Cancer (Adenocarcinoma) / Triple Negative Breast Cancer (TNBC)1
1RecruitingTreatmentHepatocellular Cancer / Liver Cancer1
1RecruitingTreatmentKRAS Activating Mutation / Recurrent Non-Small Cell Lung Carcinoma / Stage III Non-Small Cell Lung Cancer / Stage III Non-Small Cell Lung Cancer AJCC v7 / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIA Non-Small Cell Lung Cancer AJCC v7 / Stage IIIb Non-small Cell Lung Cancer / Stage IIIB Non-Small Cell Lung Cancer AJCC v71
1RecruitingTreatmentMalignant Neoplasm of Breast / Malignant Neoplasms of Digestive Organs / Malignant Neoplasms of Female Genital Organs / Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites / Malignant Neoplasms of Independent (Primary) Multiple Sites / Malignant Neoplasms of Lip Oral Cavity and Pharynx / Malignant Neoplasms of Mesothelial and Soft Tissue / Malignant Neoplasms of Respiratory and Intrathoracic Organs / Malignant Neoplasms of Thyroid and Other Endocrine Glands / Malignant Neoplasms of Urinary Tract / Neoplasms of Uncertain or Unknown Behavior1
1RecruitingTreatmentMelanoma2
1RecruitingTreatmentMultiple Myeloma (MM)1
1RecruitingTreatmentTumors, Solid1
1TerminatedTreatmentCancers1
1TerminatedTreatmentRelapsed Metastatic KRAS-Mutated Non-Small Cell Lung Cancer1
1WithdrawnTreatmentCancers2
1WithdrawnTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1WithdrawnTreatmentMelanoma2
1WithdrawnTreatmentMetastatic Melanoma1
1, 2Active Not RecruitingTreatmentMelanoma1
1, 2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1, 2Not Yet RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Lung Diseases Due to External Agents1
1, 2RecruitingTreatmentAdenocarcinoma of the Lung / Lung Cancer Metastatic / Lung Cancers / Lung carcinoma cell type unspecified stage IV / Recurrent Lung Adenocarcinoma / Recurrent Lung Cancer1
1, 2RecruitingTreatmentAdvanced Malignancy / Advanced Solid Tumors / Cancers / Melanoma / Oncology / Oncology Patients / Tumors1
1, 2RecruitingTreatmentAdvanced Malignant Solid Neoplasm / Extensive Stage Small Cell Lung Carcinoma / KRAS Gene Mutation / Metastatic Malignant Solid Neoplasm / Metastatic Solid Neoplasm / Neoplasms, Advanced Solid / NRAS Gene Mutation / Recurrent Colorectal Carcinoma / Recurrent Lung Carcinoma / Recurrent Non-Small Cell Lung Carcinoma / Recurrent Pancreatic Carcinoma / Recurrent Small Cell Lung Carcinoma / Solid Neoplasms / Stage III Colorectal Cancer / Stage III Colorectal Cancer AJCC v7 / Stage III Lung Cancer / Stage III Lung Cancer AJCC v7 / Stage III Pancreatic Cancer / Stage III Pancreatic Cancer AJCC v6 and v7 / Stage IIIA Colorectal Cancer / Stage IIIA Colorectal Cancer AJCC v7 / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIB Colorectal Cancer / Stage IIIB Colorectal Cancer AJCC v7 / Stage IIIb Non-small Cell Lung Cancer / Stage IIIC Colorectal Cancer / Stage IIIC Colorectal Cancer AJCC v7 / Stage IV Colorectal Cancer / Stage IV Colorectal Cancer AJCC v7 / Stage IV Lung Cancer / Stage IV Lung Cancer AJCC v7 / Stage IV Non-Small Cell Lung Cancer / Stage IV Pancreatic Cancer / Stage IV Pancreatic Cancer AJCC v6 and v7 / Stage IVA Colorectal Cancer / Stage IVA Colorectal Cancer AJCC v7 / Stage IVB Colorectal Cancer / Stage IVB Colorectal Cancer AJCC v7 / Unresectable Malignant Neoplasm1
1, 2RecruitingTreatmentColorectal Cancers1
1, 2RecruitingTreatmentColorectal Cancers / Malignant Neoplasm of Pancreas / Tumors, Solid1
1, 2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
1, 2RecruitingTreatmentMelanoma3
1, 2RecruitingTreatmentMelanoma / Tumors, Solid1
1, 2RecruitingTreatmentMetastatic Melanoma1
1, 2RecruitingTreatmentMetastatic Melanoma / Recurrent Melanoma / Solid Neoplasms / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIA Skin Melanoma / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIB Skin Melanoma / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IIIC Skin Melanoma / Stage IV Cutaneous Melanoma AJCC v6 and v7 / Stage IV Skin Melanoma1
1, 2SuspendedTreatmentAdult Solid Neoplasm / Recurrent Colon Carcinoma / Recurrent Melanoma / Recurrent Ovarian Carcinoma / Stage IIIC Colon Cancer / Stage IIIC Ovarian Cancer / Stage IIIC Skin Melanoma / Stage IV Skin Melanoma1
2Active Not RecruitingTreatmentAdult Cholangiocarcinoma / Advanced Adult Hepatocellular Carcinoma / BCLC Stage C Adult Hepatocellular Carcinoma / BCLC Stage D Adult Hepatocellular Carcinoma / Hilar Cholangiocarcinoma / Localized Non-Resectable Adult Liver Carcinoma / Recurrent Adult Liver Carcinoma / Recurrent Childhood Liver Cancer / Recurrent Extrahepatic Bile Duct Carcinoma / Recurrent Gallbladder Carcinoma / Stage II Gallbladder Cancer / Stage III Childhood Hepatocellular Carcinoma / Stage IIIA Gallbladder Cancer / Stage IIIB Gallbladder Cancer / Stage IV Childhood Hepatocellular Carcinoma / Stage IV Distal Bile Duct Cancer / Stage IVA Gallbladder Cancer / Stage IVB Gallbladder Cancer / Unresectable Extrahepatic Bile Duct Carcinoma1
2Active Not RecruitingTreatmentCancers3
2Active Not RecruitingTreatmentEstrogen Receptor Negative / HER2/Neu Negative / Invasive Breast Carcinoma / Progesterone Receptor Negative / Recurrent Breast Carcinoma / Stage IV Breast Cancer / Triple-Negative Breast Carcinoma1
2Active Not RecruitingTreatmentFollicular Thyroid Cancer / Insular Thyroid Cancer / Recurrent Thyroid Cancer / Thyroid Papillary Carcinoma1
2Active Not RecruitingTreatmentMalignant Melanoma1
2Active Not RecruitingTreatmentMelanoma1
2Active Not RecruitingTreatmentMelanoma and Brain Metastases1
2Active Not RecruitingTreatmentMetastatic Radioactive Iodine Refractory Thyroid Cancer Patients With RAS or BRAF Mutation1
2Active Not RecruitingTreatmentRecurrent Adult Acute Myeloid Leukemia / Untreated Adult Acute Myeloid Leukemia1
2Active Not RecruitingTreatmentRecurrent Plasma Cell Myeloma / Refractory Plasma Cell Myeloma1
2Active Not RecruitingTreatmentRecurrent Uveal Melanoma / Stage IV Uveal Melanoma1
2Active Not RecruitingTreatmentTumors, Solid1
2CompletedDiagnosticMelanoma1
2CompletedTreatmentCancers4
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentMelanoma1
2CompletedTreatmentMelanoma and Brain Metastases1
2CompletedTreatmentMouth Neoplasms / Neoplasms, Oral1
2Not Yet RecruitingTreatmentAnaplastic Astrocytoma (AA) / Anaplastic Ependymoma / Anaplastic Ganglioglioma / Anaplastic Hemangiopericytoma / Anaplastic Oligoastrocytoma / Anaplastic Oligodendroglioma (AO) / Choroid Plexus Carcinoma / Giant Cell Glioblastoma / Glioblastomas / Gliosarcoma / Malignant Meningloma / Medulloblastomas / MPNST / Perineurioma / Pineal Parenchymal Tumor / Pinealoblastoma / PNET / Rhabdoid Tumors1
2Not Yet RecruitingTreatmentColorectal Cancers1
2Not Yet RecruitingTreatmentHormone-Resistant Prostate Cancer / Metastatic Hormone Refractory Prostate Cancer / Recurrent Prostate Carcinoma / Stage IV Prostate Cancer1
2Not Yet RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
2Not Yet RecruitingTreatmentMelanoma / Metastatic Brain Tumors1
2Not Yet RecruitingTreatmentMetastatic Melanoma1
2RecruitingTreatmentActivating RAS Mutation / Juvenile Myelomonocytic Leukemia / Monosomy 7 / Neurofibromatosis Type 1 / NF1 Gene Mutation / PTPN11 Gene Mutation / Splenomegaly1
2RecruitingTreatmentAdenocarcinomas / Malignant Neoplasm of Pancreas1
2RecruitingTreatmentAdvanced Malignant Neoplasm / Advanced Malignant Solid Neoplasm / Bladder Carcinoma / Carcinoma, Breast / Carcinoma, Colorectal / Carcinoma, Pancreatic / Cervical Carcinoma / Colon Carcinoma / Endometrial Carcinoma / Gastric Carcinoma / Gliomas / Head and Neck Carcinoma / Liver and Intrahepatic Bile Duct Carcinoma / Lung, Carcinoma / Malignant Lymphomas / Malignant Uterine Neoplasm / Melanoma / Oesophageal Carcinoma / Ovarian Carcinoma / Plasma Cell Myeloma / Prostate Cancer / Rectal Carcinoma / Recurrent Bladder Carcinoma / Recurrent Breast Carcinoma / Recurrent Cervical Carcinoma / Recurrent Colon Carcinoma / Recurrent Colorectal Carcinoma / Recurrent Esophageal Carcinoma / Recurrent Gastric Carcinoma / Recurrent Gliomas / Recurrent Head and Neck Carcinoma / Recurrent Liver Carcinoma / Recurrent Lung Carcinoma / Recurrent Lymphoma / Recurrent Malignant Solid Neoplasm / Recurrent Melanoma / Recurrent Ovarian Carcinoma / Recurrent Pancreatic Carcinoma / Recurrent Plasma Cell Myeloma / Recurrent Prostate Carcinoma / Recurrent Rectal Carcinoma / Recurrent Skin Carcinoma / Recurrent Solid Neoplasm / Recurrent Thyroid Gland Carcinoma / Recurrent Uterine Corpus Carcinoma / Refractory Lymphomas / Refractory Malignant Neoplasm / Refractory Malignant Solid Neoplasm / Refractory Plasma Cell Myeloma / Renal Carcinoma / Skin Carcinoma / Solid Neoplasms / Thyroid Gland Carcinoma / Uterine Corpus Cancer1
2RecruitingTreatmentAdvanced Malignant Solid Neoplasm / Neoplasms / Neoplasms, Advanced Solid / Recurrent Malignant Solid Neoplasm / Recurrent Solid Neoplasm1
2RecruitingTreatmentBRAF Gene Mutation / Poorly Differentiated Thyroid Gland Carcinoma / RAS Family Gene Mutation / Recurrent Thyroid Gland Carcinoma / Stage IV Thyroid Gland Follicular Carcinoma / Stage IV Thyroid Gland Papillary Carcinoma / Stage IVA Thyroid Gland Follicular Carcinoma / Stage IVA Thyroid Gland Papillary Carcinoma / Stage IVB Thyroid Gland Follicular Carcinoma / Stage IVB Thyroid Gland Papillary Carcinoma / Stage IVC Thyroid Gland Follicular Carcinoma / Stage IVC Thyroid Gland Papillary Carcinoma1
2RecruitingTreatmentBRAF V600E Mutation Present / BRAF V600K Mutation Present / Recurrent Melanoma / Stage III Cutaneous Melanoma AJCC v7 / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIA Skin Melanoma / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIB Skin Melanoma / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IIIC Skin Melanoma / Stage IV Cutaneous Melanoma AJCC v6 and v7 / Stage IV Skin Melanoma / Stages III Skin Melanoma1
2RecruitingTreatmentBRAF Wildtype / Colorectal Cancers / KRAS Wildtype / NRAS Wildtype1
2RecruitingTreatmentCancers2
2RecruitingTreatmentCancers / Neoplasia / Neoplasms / Tumors1
2RecruitingTreatmentEpithelioid Hemangioendothelioma1
2RecruitingTreatmentKRAS Gene Mutation / Recurrent Non-Small Cell Lung Carcinoma / Stage IV Non-Small Cell Lung Cancer / Stage IV Non-Small Cell Lung Cancer AJCC v71
2RecruitingTreatmentMalignant Melanoma1
2RecruitingTreatmentMalignant Melanoma Stage IV / Melanoma / Metastatic Melanoma1
2RecruitingTreatmentMelanoma2
2RecruitingTreatmentMetastatic Melanoma1
2RecruitingTreatmentProstate Cancer1
2RecruitingTreatmentRecurrent Melanoma / Stage IIIB Melanoma / Stage IIIc Melanoma / Stage IV Melanoma1
2SuspendedTreatmentBRAF V600E Mutation1
2TerminatedOtherRecurrent Melanoma / Stage IIB Melanoma (Locally Advanced) / Stage IIC Melanoma (Locally Advanced) / Stage IIIA Melanoma / Stage IIIB Melanoma / Stage IIIc Melanoma / Stage IV Melanoma (Limited, Resectable)1
2TerminatedTreatmentCervical Cancers1
2Unknown StatusTreatmentMelanoma1
2WithdrawnTreatmentCancers / GNA11 Mutation-positive Metastatic Melanoma / GNAQ Mutation-positive Metastatic Melanoma / Metastatic Uveal Melanoma1
2WithdrawnTreatmentGastrointestinal Stromal Tumors1
2WithdrawnTreatmentMultiple Myeloma (MM)1
2, 3RecruitingTreatmentLow Grade Ovarian Serous Adenocarcinoma / Micropapillary Serous Carcinoma / Ovarian Serous Adenocarcinoma / Primary Peritoneal Serous Adenocarcinoma / Recurrent Ovarian Carcinoma / Recurrent Primary Peritoneal Carcinoma1
3Active Not RecruitingTreatmentMelanoma3
3CompletedTreatmentMelanoma1
3RecruitingTreatmentBRAF NP_004324.2:p.V600X / BRAF V600E Mutation Present / BRAF V600K Mutation Present / Metastatic Melanoma / Recurrent Melanoma / Stage III Cutaneous Melanoma AJCC v7 / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIA Skin Melanoma / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIB Skin Melanoma / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IIIC Skin Melanoma / Stage IV Cutaneous Melanoma AJCC v6 and v7 / Stage IV Skin Melanoma / Stages III Skin Melanoma1
3RecruitingTreatmentMelanoma2
4Not Yet RecruitingTreatmentHigh Grade Glioma (HGG) / Lung Cancer Non-Small Cell Cancer (NSCLC) / Melanoma / Rare Cancers / Tumors, Solid1
4Not Yet RecruitingTreatmentMelanoma1
Not AvailableCompletedNot AvailableMalignant Melanoma Stage IIIc / Malignant Melanoma Stage IV1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral0.5 mg
TabletOral1 mg
TabletOral2 mg
Tablet, film coatedOral.5 mg/1
Tablet, film coatedOral0.5 mg
Tablet, film coatedOral1 mg/1
Tablet, film coatedOral2 mg/1
Tablet, film coatedOral2 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8703781No2010-10-152030-10-15Us
US8835443No2005-09-132025-09-13Us
US9271941No2012-01-282032-01-28Us
US9155706No2012-01-282032-01-28Us
US7378423No2005-09-132025-09-13Us
US8580304No2012-01-282032-01-28Us
US8952018No2010-10-152030-10-15Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0307 mg/mLALOGPS
logP3.45ALOGPS
logP3.18ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)12.6ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area102.06 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity156.38 m3·mol-1ChemAxon
Polarizability55.43 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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Acetanilide / Pyridopyrimidine / N-acetylarylamine / Anilide / N-arylamide / Aniline or substituted anilines / Aminopyridine / Fluorobenzene / Halobenzene / Iodobenzene
show 34 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organofluorine compound, organoiodine compound, acetamides, aromatic amine, cyclopropanes, ring assembly, pyridopyrimidine (CHEBI:75998)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
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. [PubMed:23432625]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
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. [PubMed:23432625]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
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

Drug created on June 24, 2013 15:36 / Updated on November 22, 2017 12:37