Home >> Dabrafenib Mesylate (GSK-2118436)
Related Products
Dabrafenib Mesylate (GSK-2118436)
Inhibitor of BRAF(V600) mutants

Catalog No.A3347
Size Price Stock Qty
10mM (in 1mL DMSO)
$65.00
In stock
Dabrafenib (GSK2118436) Evaluation Sample
$28.00
In stock
10mg
$70.00
In stock
50mg
$150.00
In stock
100mg
$240.00
In stock

Tel: +1-832-696-8203

Email: [email protected]

Worldwide Distributors

      

Sample solution is provided at 25 µL, 10mM.

Quality Control

Chemical structure

Dabrafenib Mesylate (GSK-2118436)

Related Biological Data

Dabrafenib
Growth of Colo 205 tumor xenografts was measured in mice during and for a period following oral q.d. x 14 treatment with 0, 3, 10, 30, and 100 mg/kg dabrafenib. Mean tumor volumes are plotted with their standard error mean and 4 partial regressions out of 8 mice were observed at the 100 mg/kg dose after the 14-day treatment period. The 14-day period of dosing is indicated by the shaded gray bar.

Biological Activity

Targets Raf          
IC50 3.2/0.8/5.0 nM (B-Raf/B-RafV600E/ c-Raf)          

Protocol

Cell experiment [1]:

Cell lines

M257 wild-type BRAF, LCP BRAFV600R and WM266 BRAFV600D melanoma cell lines.

Preparation method

Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reaction Conditions

3-100 nM; 72 h

Applications

Dabrafenib remarkably inhibits cell proliferation and phosphorylated ERK in both melanoma cell lines carrying a mutated BRAF.

Animal experiment [2]:

Animal models

Female CD1 nu/nu mice xenografted BRAFV600E (A375P) human tumor.

Dosage form

30 mg/kg; 14 days; dosed orally once daily.

Preparation method

0.5% hydroxypropylmethylcellulose, 0.2% Tween 80 in pH 8.0 distilled water; 0.2 mL per 20 g of bodyweight.

Applications

Dabrafenib is orally bioavailable, reduces pERK and inhibits tumor growth. Dabrafenib reduces pERK and Ki67 by 89% and 28% respectively and increases p27 by 54%.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Gentilcore G, Madonna G, Mozzillo N, et al. Effect of dabrafenib on melanoma cell lines harbouring the BRAF(V600D/R) mutations. BMC Cancer, 2013, 13: 17.

[2]. King AJ, Arnone MR, Bleam MR, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One, 2013, 8(7): e67583.

Dabrafenib Mesylate (GSK-2118436) Dilution Calculator

Concentration (start)
x
Volume (start)
=
Concentration (final)
x
Volume (final)
 
 
 
C1
V1
C2
V2

calculate

Dabrafenib Mesylate (GSK-2118436) Molarity Calculator

Mass
=
Concentration
x
Volume
x
MW*
 
 
 
g/mol

calculate

Chemical Properties

Cas No. 1195768-06-9 SDF Download SDF
Synonyms GSK-2118436 Mesylate;GSK2118436 Mesylate;GSK 2118436 Mesylate;GSK 2118436B,Tafinlar,
Chemical Name N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide;methanesulfonic acid
Canonical SMILES CC(C)(C)C1=NC(=C(S1)C2=NC(=NC=C2)N)C3=C(C(=CC=C3)NS(=O)(=O)C4=C(C=CC=C4F)F)F.CS(=O)(=O)O
Formula C24H24F3N5O5S3 M.Wt 615.67
Solubility >30.8mg/mL in DMSO Storage Store at -20°C
Shipping Condition Evaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

Research Update

1. Concomitant oral and intravenous pharmacokinetics of dabrafenib, a BRAF inhibitor, in patients with BRAF V600 mutation-positive solid tumors. J Clin Pharmacol. 2013 Sep;53(9):955-61. doi: 10.1002/jcph.127. Epub 2013 Jul 12.
Abstract
The pharmacokinetic parameters of dabrafenib, an inhibitor of human BRAF, CRAF and mutant BRAF kinases, have determined in four patients with BRAF mutation-positive solid tumors, in which the least squares mean absolute bioavailability, median T(max) after oral administration, the geometric mean terminal half-life, the geometric mean clearance and volume of distribution after IV administration were 94.5%, 2.0 hours, 4.8 hours, 12.0 L/h and 45.5 L respectively.
2. Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib. Cancer. 2014 Feb 15;120(4):530-6. doi: 10.1002/cncr.28445. Epub 2013 Nov 5.
Abstract
Dabrafenib has been assessed for IC and EC patterns of response and progression in the treatment of patients with active melanoma brain metastases.
3. Population Pharmacokinetics of Dabrafenib, a BRAF Inhibitor: Effect of Dose, Time, Covariates, and Relationship With Its Metabolites. J Clin Pharmacol. 2014 Jan 9. doi: 10.1002/jcph.263. [Epub ahead of print]
Abstract
The population pharmacokinetics of dabrfenib, a BRAF inhibitor, were characterized, in which steady state was achieved in 14 days following a 150 mg BID dose with total clearance, induction half-life and pre-dose concentration of 34.3 L/h, 67 hours and 46.6 ng/mL respectively. Capsule shell, sex and weight did affect dabrafenib exposure; while age, renal and hepatic impairment didn’t.
4. Dabrafenib in the treatment of advanced melanoma. Drugs Today (Barc). 2013 Jun;49(6):377-85. doi: 10.1358/dot.2013.49.6.1968669.
Abstract
Dabrafenib exhibits efficacy against BRAF V600E-mutated melanoma, non-V600E BRAF-mutated disease and brain metastases, where 50% response rate and 6 months progression-free survival were observed in dabrafenib-treated melanoma patients with BRAF V600E mutations. The combination of dabrafenib and trametinib showed synergistic effects to improve both the progression-free survival and overall survival of melanoma patients.
5. Dabrafenib Therapy for Advanced Melanoma. Ann Pharmacother. 2013 Nov 20. [Epub ahead of print]
Abstract
Clinical development and characteristics of dabrafenib were summarized and compared to vemurafenib.

Background

GSK2118436 is a selective BRAF V600E inhibitor. BRAF encodes a proto-oncogene B-Raf also known as serine/threonine protein kinase B-Raf. It is critical in regulating the MAPK/ERK signaling pathway. BRAF mutations frequently occur in many human cancers. [1, 2] BRAF V600E mutant is constitutively active, allowing MAPK/ERK activation independent of upstream cues. [3]

GSK2118436 binds to Raf family kinases and inhibits their activity. It is highly selective against B-Raf V600E with IC50 of 0.8 nM, compared to wild type B-Raf and c-Raf with IC50s of 3.2 nM and 5.0 nM, respectively. [4]

GSK2118436 treatment shows selective inhibition of MAPK/ERK activation, proliferation, transformation and tumorigenicity. FDA approved GSK2118436 as a single agent treatment for advanced melanoma with BRAF V600E mutation on May 30, 2013.

GSK2118436 can be taken orally.

References:
[1]Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S, Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T, Yamashita S. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J. Clin. Endocrinol. Metab. 2003; 88 (9): 4393–7.
[2]Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, Iacopetta B, Soong R. Detection of BRAF V600E mutation by pyrosequencing. Pathology 2008; 40 (3): 295–8.
[3]Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417: 949-954.
[4]Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G, Villanueva J, Hart LS, Levi S, Hu J, Zhang G, Lazova R, Klump V, Pawelek JM, Xu X, Xu W, Schuchter LM, Davies MA, Herlyn M, Winkler J, Koumenis C, Amaravadi RK. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest. 2014; 124(3): 1406-17.