dabrafenib   Click here for help

GtoPdb Ligand ID: 6494

Synonyms: GSK2118436 | GSK2118436A | Tafinlar®
Approved drug PDB Ligand
dabrafenib is an approved drug (FDA and EMA (2013))
Compound class: Synthetic organic
Comment: Dabrafenib is a Type-1.5 kinase inhibitor.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 147.48
Molecular weight 519.1
XLogP 3.91
No. Lipinski's rules broken 0
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Canonical SMILES Nc1nccc(n1)c1sc(nc1c1cccc(c1F)NS(=O)(=O)c1c(F)cccc1F)C(C)(C)C
Isomeric SMILES Nc1nccc(n1)c1sc(nc1c1cccc(c1F)NS(=O)(=O)c1c(F)cccc1F)C(C)(C)C
InChI InChI=1S/C23H20F3N5O2S2/c1-23(2,3)21-30-18(19(34-21)16-10-11-28-22(27)29-16)12-6-4-9-15(17(12)26)31-35(32,33)20-13(24)7-5-8-14(20)25/h4-11,31H,1-3H3,(H2,27,28,29)
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Summary of Clinical Use Click here for help
Dabrafenib is a kinase inhibitor approved for the treatment of patients with unresectable or metastatic melanoma with BRAF mutations as detected by an FDA-approved test and should not be used to treat patients with wildytpe BRAF tumors.
Marketed formulations contain dabrafenib mesylate (PubChem CID 44516822).
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.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Dabrafenib potently inhibits (IC50 in low nanomolar concentrations) constitutively active BRAF kinase with mutations V600E (VAR_018629)., V600K, and V600D in vitro. The mechanism of tumor inhibition is thought to be via dabrafenib-induced inhibition of phosphorylated ERK resulting in a decrease in cell proliferation. Downstream mediators of the MAPK pathway are also inhibited. Dabrafenib also inhibits wild-type BRAF and CRAF kinases at low IC50 concentrations and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations.
Pharmacokinetics Click here for help
Peak plasma concentration is reached 2 hours after oral administration. It is recommended to dose in the fasted state. Mean absolute bioavailability of oral dabrafenib is 95%. Dabrafenib is 99.7% bound to human plasma proteins.
Dabrafenib is excreted in urine and bile as carboxy-dabrafenib (by the sequential actions of CYP2C8 and CYP3A4). Desmethyl-dabrafenib is a decarboxylation metabolite that may be reabsorbed from the gut. The parent drug and the hydroxy- metabolite have similar terminal half-lives (10 hours), but the carboxy- and desmethyl- metabolites have extended half-lives (21-22 hours). Both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib.
Excretion of dabrafenib is primarily via feces (71%) with urinary excretion accounting for 23% ( recovered as metabolites only).
Population pharmacokinetics
There are no clinically relevant differences in exposure to dabrafenib associated with age, gender or weight. The pharmacokinetics of dabrafenib have not been studied in pediatric patients.
Organ function impairment
Mild or moderate renal impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with severe renal impairment. Mild hepatic impairment has no effect on systemic exposure to dabrafenib and its metabolites. No data are available in patients with moderate to severe hepatic impairment.
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