Dabrafenib

BRAF Inhibitor

DB08912

Approved Indication

Dabrafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

5 Targets

16 Resistance Mutations

59 References

4XV2 Structure Loaded

3D Structure PDB: 4XV2

Switch structure: RCSB ↗

Protein Targets

BRAF P15056 ✓ 3 PDB RAF1 P04049 ✓ LIMK1 P53667 NEK11 Q8NG66 SIK1 P57059

Mechanism of Action

Dabrafenib is an inhibitor of some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Dabrafenib also inhibits wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM, respectively, and other kinases such as SIK1, NEK11, and LIMK1 at higher concentrations. Some mutations in the BRAF gene, including those that result in BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth.

Resistance Mutations — 64 resistance samples observed in COSMIC

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CDKN2A

p.0 5

KRAS

p.G12C 5

MAP2K1

p.E203K 5 p.E27K 1 p.G128D 4 p.K57E 5

MAP2K2

p.C125S 5 p.C28S p.E110K p.E207K 5 p.N126D 3 p.N29D p.Q60P 5

NRAS

p.G12D 5 p.Q61K 5 p.Q61R 5

Resistance mutations sourced from COSMIC Drug Resistance database. Cyan = on-target · Amber = off-target · numbered badge = PubMed references for that mutation

Details

DrugBank ID DB08912 ↗

Approval Date 2013-06-10

Molecular Weight 519.562 g/mol

Drug Class BRAF Inhibitor

ATC Codes L01XE23

Synonyms Dabrafenib

PubChem CID: 44462760 ↗

ChEMBL CHEMBL2028663 ↗

SMILES

CC(C)(C)C1=NC(=C(S1)C1=NC(N)=NC=C1)C1=C(F)C(NS(=O)(=O)C2=C(F)C=CC=C2F)=CC=C1

ADMET Profile

Computing properties…

Drug References (DrugBank)

PMID:23621583