DABRAFENIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H20F3N5O2S2
Molecular Weight	519.562
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC(C)(C)C1=NC(=C(S1)C2=NC(N)=NC=C2)C3=CC=CC(NS(=O)(=O)C4=C(F)C=CC=C4F)=C3F

InChI

InChIKey=BFSMGDJOXZAERB-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description

Dabrafenib is a selective, orally bioavailable inhibitor of Mutant BRAF protein kinase with potential antineoplastic activity. Dabrafenib inhibits 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. BRAF belongs to the the raf/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/ERKs signaling pathway, which may be constitutively activated due to BRAF gene mutations. Mutations in BRAF are associated with increased growth and proliferation of cancer cells. By inhibiting BRAF kinase dabrafenib negatively regulates the proliferation of tumor cells which contain a mutated BRAF gene. Dabrafenib (in combination with trametinib or alone) is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase B-raf 20	Inhibitor 8,297		3.2 nM [IC50]

Conditions

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

C_max

Value	Dose	Co-administered	Analyte	Population
2497.4 ng/mL	300 mg 2 times / day multiple, oral	TRAMETINIB	DABRAFENIB plasma	Homo sapiens
806 ng/mL	300 mg 2 times / day multiple, oral		DABRAFENIB plasma	Homo sapiens
1478 ng/mL	150 mg 2 times / day multiple, oral		DABRAFENIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
13485.6 ng × h/mL	300 mg 2 times / day multiple, oral	TRAMETINIB	DABRAFENIB plasma	Homo sapiens
2619 ng × h/mL	300 mg 2 times / day multiple, oral		DABRAFENIB plasma	Homo sapiens
4341 μg × h/mL	150 mg 2 times / day multiple, oral		DABRAFENIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.9 h	300 mg 2 times / day multiple, oral	TRAMETINIB	DABRAFENIB plasma	Homo sapiens
5.2 h	300 mg 2 times / day multiple, oral		DABRAFENIB plasma	Homo sapiens
8 h	150 mg 2 times / day multiple, oral		DABRAFENIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.3%	150 mg 2 times / day multiple, oral		DABRAFENIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187	Disc. AE: Constipation, Hepatic pain...
150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187	Disc. AE: Pain, Hyperkeratosis...
150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187	Disc. AE: Hyperhidrosis, Migraine...
150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187	Disc. AE: Oropharyngeal pain, Malaise...
150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187	Disc. AE: Back pain, Muscle spasms...

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AEs

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AE	Significance	Dose	Population
Tricuspid valve disease	2 patients Disc. AE	150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187
Constipation	serious, 1 patient Disc. AE	150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187
Hepatic pain	serious, 1 patient Disc. AE	150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187
Myocardial infarction	serious, 1 patient Disc. AE	150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187
Muscular weakness	serious, 2 patients Disc. AE	150 mg 2 times / day steady, oral Recommended	unhealthy, 53 years (range: 22-93 years) n = 187

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Overview

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

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 911 CYP2C19 1,478 CYP1A2 1,524 BCRP 699 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 P-gp 1,461	CYP2C8 693 CYP2C19 991 P-gp 1,537	CYP1A2 701 CYP2B6 547

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inducer 1,573	no
P-gp 1,650	inhibitor 3,277	no
OATP1B1 803	inhibitor 3,277	yes [IC50 1.4 uM]
CYP3A4 1,925	inhibitor 3,277	yes [IC50 16 uM]
CYP2C19 1,553	inhibitor 3,277	yes [IC50 22 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP2C8 693	substrate 3,367	major	unknown (co-administration study)
CYP3A4 1,737	substrate 3,367	major	yes (co-administration study)
CYP2C19 991	substrate 3,367	minor
CYP2C9 1,037	substrate 3,367	minor
P-gp 1,537	substrate 3,367	yes	unlikely

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Tox targets

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

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:75045	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:75045
ChemicalBook	CB32604230	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB32604230
MolPort	MolPort-028-720-422	https://www.molport.com/shop/molecule-link/MolPort-028-720-422
Selleck Chemicals	dabrafenib-gsk2118436a	http://www.selleckchem.com/products/dabrafenib-gsk2118436a.html
ZINC	ZINC000068153186	http://zinc15.docking.org/substances/ZINC000068153186

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PubMed

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Title	Date	PubMed
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.	2010 Sep 30	20823850
BRAF inhibitor activity in V600R metastatic melanoma.	2013 Mar	23237741

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage regimens are: 150 mg orally taken twice daily, approximately 12 hours apart, as a single agent or 150 mg orally taken twice daily, approximately 12 hours apart, in combination with trametinib 2 mg orally taken once daily.

Route of Administration: Oral

In Vitro Use Guide

A375, SK-MEL-28, WM239 and SK-MEL-5 cells with 2.5, 5 and 10 nM dabrafenib for 72 hours. Dabrafenib treatment induced massive Mcl-1 expression at all the three concentrations. The IC50 of dabrafenib in A375, SK-MEL-28 and WM-239 was 5nM, 2nM and 6nM respectively. In dabrafenib resistant A375, SK-MEL-28 and WM-239 cells, which were denoted as A375-DR, SK-MEL-28-DR and WM-239-DR that were incubated with up to 300 nM inhibitor concentrations the IC50s were greater than 100 nM indicating more than 30-fold resistance.

Show entries

Name

Type

Language

DABRAFENIB

Official Name

English

Dabrafenib [WHO-DD]

Common Name

English

GSK-2118436A

Code

English

DABRAFENIB [MI]

Common Name

English

GSK2118436A

Code

English

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Classification Tree

Code System

Code

Designated

FDA ORPHAN DRUG

775820

Designated/Approved

FDA ORPHAN DRUG

521616

Protein kinase inhibitors

WHO-ATC

L01XE23

Antineoplastic Enzyme Inhibitor

NCI_THESAURUS

C155322

Designated/Approved

FDA ORPHAN DRUG

495915

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Show entries

Code System

Code

Type

Description

NDF-RT

N0000190108

PRIMARY

Organic Anion Transporting Polypeptide 1B3 Inhibitors [MoA]

MERCK INDEX

m11719

PRIMARY

CAS

1195765-45-7

PRIMARY

NDF-RT

N0000185506

PRIMARY

Cytochrome P450 3A4 Inducers [MoA]

CHEBI

75045

PRIMARY

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ACTIVE MOIETY


					QGP4HA4G1B

DABRAFENIB

METABOLITE (PARENT)


					K8LO461TMR

CARBOXY DARAFENIB

METABOLITE ACTIVE (PARENT)


					3EHQ1EWE0D

DESMETHYL DABRAFENIB

SALT/SOLVATE (PARENT)


					B6DC89I63E

DABRAFENIB MESYLATE

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator