Description Synthetic Methods Biological activity How to use Major Side Effects In vitro In vivo References
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Dabrafenib

Description Synthetic Methods Biological activity How to use Major Side Effects In vitro In vivo References
Product Name
Dabrafenib
CAS No.
1195765-45-7
Chemical Name
Dabrafenib
Synonyms
Dabrafenib (GSK2118436);N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide;N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide;CS-658;abrafenib;Dabrafenib;Darla fini;GSK2118436A;Debrafenib API;Dabrafenib Base
CBNumber
CB32604230
Molecular Formula
C23H20F3N5O2S2
Formula Weight
519.56
MOL File
1195765-45-7.mol
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Dabrafenib Property

Melting point:
214-216oC
Boiling point:
653.7±65.0 °C(Predicted)
Density 
1.443
storage temp. 
-20°C
solubility 
Soluble in DMSO (up to 30 mg/ml with warming), or in Ethanol (up to 1 mg/ml with warming).
form 
White solid.
pka
6.62±0.10(Predicted)
color 
Off-white
Stability:
Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
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)
InChIKey
BFSMGDJOXZAERB-UHFFFAOYSA-N
SMILES
C1(S(NC2=CC=CC(C3=C(C4C=CN=C(N)N=4)SC(C(C)(C)C)=N3)=C2F)(=O)=O)=C(F)C=CC=C1F
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Safety

HS Code 
29350090
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Hazard and Precautionary Statements (GHS)

Symbol(GHS)
Signal word
Warning
Hazard statements

H361Suspected of damaging fertility or the unborn child

H400Very toxic to aquatic life

H411Toxic to aquatic life with long lasting effects

Precautionary statements

P201Obtain special instructions before use.

P202Do not handle until all safety precautions have been read and understood.

P273Avoid release to the environment.

P281Use personal protective equipment as required.

P308+P313IF exposed or concerned: Get medical advice/attention.

P391Collect spillage. Hazardous to the aquatic environment

P405Store locked up.

P501Dispose of contents/container to..…

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N-Bromosuccinimide Price

Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
5mg
Price
$36
Updated
2024/03/01
Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
10mg
Price
$69
Updated
2024/03/01
Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
100 mg
Price
$393
Updated
2024/03/01
Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
50mg
Price
$233
Updated
2024/03/01
Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
25mg
Price
$171
Updated
2023/01/06
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Dabrafenib Chemical Properties,Usage,Production

Description

N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide is well known as dabrafenib. It is a drug for the treatment of cancers associated with a mutated version of the gene BRAF. Dabrafenib acts as an inhibitor of the associated enzyme B-Raf, which plays a role in the regulation of cell growth. Dabrafenib has clinical activity with a manageable safety profile in clinical trials of phase-I and -II in patients with BRAF(V600)-mutated metastatic melanoma1,2. Its mechanism of action is acted as a Protein Kinase Inhibitor, and Cytochrome P450 3A4 Inducer, and Cytochrome P450 2B6 Inducer, and Cytochrome P450 2C8 Inducer, and Cytochrome P450 2C9 Inducer, and Cytochrome P450 2C19 Inducer, and Organic Anion Transporting Polypeptide 1B1 Inhibitor, and Organic Anion Transporting Polypeptide 1B3 Inhibitor, and Organic Anion Transporter 1 Inhibitor, and Organic Anion Transporter 3 Inhibitor, and Breast Cancer Resistance Protein Inhibitor3,4. It is not indicated for the treatment of patients with wild-type BRAF melanoma or wild-type BRAF NSCLC. MEKINIST is not indicated for the treatment of patients with melanoma who have progressed on prior BRAF-inhibitor therapy5.

Synthetic Methods

The key step in the synthesis of Dabrafenib is the construction of the 1,3-thiazole ring, which is usually carried out by the closing ring directly of thioamide (as a 1,3-binuclear reagent) and anα-carbonyl halide (as a 1,2-amphiphilic reagent). Sulfonyl chloride 1 and aniline 2 gave sulfonamide 3 under basic conditions. Methyl pyrimidine 4 with non-nucleophilic strong alkali LiHMDS pull out the acid proton on the methyl and react with 3 to obtain 5, and the latter has α-bromination with NBS to obtain 1,2-amphiphilic reagent 6, and then 6 reacts with 1 , 3-parent nucleotides 7 to close the ring to obtain 8, and finally reacts with ammonia to obtain Dabrafenib.

Figure 1: synthetic route of Dabrafenib

Biological activity

Dabrafenib (GSK2118436) is a mutant BRAFV600 specific inhibitor with an IC50 of 0.8 nM, and effects for B-Raf (wt) and c-Raf is 4 and 6 fold lower respectively.

How to use

It is usually taken twice a day on an empty stomach, 1 hour before or 2 hours after a meal. Take dabrafenib about 12 hours apart at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Do not stop taking dabrafenib without talking to your doctor.
Swallow the capsules whole; do not split, chew, or crush them.
Your doctor may adjust your dose of dabrafenib depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.

Major Side Effects

The following side effects are common (occurring in greater than 30%) for patients taking dabrafenib :

  • Hyperglycemia
  • Hyperkeratosis
  • Hypophosphatemia
  • Headache

These side effects are less common side effects (occurring in about 10-29%) of patients receiving dabrafenib:
  • Fever
  • Joint pain
  • Papilloma (warts/growths)
  • Hair loss
  • Hand-foot syndrome (Palmar-planter erythrodyesthesia)
  • Increased Alkaline phosphatase
  • Rash
  • Back pain
  • Cough
  • Muscle aches
  • Constipation
  • Nasopharyngitis

In vitro

Dabrafenib is selective for Raf kinases and is 400 times more active against B-Raf than other tested 91% kinases. Dabrafenib inhibits B-RafV600E kinase, resulting in reduced phosphorylation of ERK and inhibition of cell proliferation. The cells stagnate in the G1 phase in cancer cells that specifically encode mutated B-RafV600E.

In vivo

Dabrafenib (oral) inhibits the growth of B-RafV600E mutated melanoma (A375P). Dabrafenib (oral) also inhibits tumor growth, subcutaneously injecting colon cancer (Colo205) in immunocompromised mice.

References

  1. https://www.caymanchem.com/product/16989
  2. https://en.wikipedia.org/wiki/Dabrafenib
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Dabrafenib
  4. Menzies, A. M., and G. V. Long. "Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. " Clinical Cancer Research 20.8(2014): 2035-2043.
  5. https://www.hcp.novartis.com/products/tafinlar-mekinist/

Description

In May 2013, the US FDA approved dabrafenib (also referred to as GSK 2118436) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by a FDA-approved test. Dabrafenib was identified from a screen of an oncology-directed kinase collection, followed by extensive structure–activity relationships (SAR) on an initial thiazole lead. Dabrafenib is a potent inhibitor of B-BRAFV600E kinase (IC50=0.65 nM) compared to its potency against wild-type B-raf (IC50=3.2 nM). It also inhibits other kinases (e.g., CRAF) and other mutant B-raf kinases (BRAFV600E and BRAFV600D) with enzyme IC50s of <5 nM and is fairly selective versus a panel of 270 kinases. Consistent with its in vitro activity, oral administration of dabrafenib inhibits the growth of B-RafV600E mutant melanoma (A375P) and colon cancer (Colo205) human tumor xenografts growing subcutaneously in immunocompromised mice. Key steps in the synthesis of dabrafenib are condensation of an aryl sulfonamide ester with the lithium anion of 2-chloro-4-methylpyrimidine to generate a ketone intermediate and bromination of the ketone intermediate with N-bromosuccinamide followed by cyclization with tert-butyl thioamide to afford the desired thiazole core.

Originator

GlaxoSmithKline (United States)

Uses

Dabrafenib is an inhibitor of mutated BRAF kinase and has clinical activity with a manageable safety profile in clinical trials of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma.

Definition

ChEBI: An organofluorine compound and antineoplastic agent, used as its mesylate salt in treatment of metastatic melanoma.

brand name

Tafinlar

General Description

Class: dual threonine/tyrosine kinase; Treatment: melanoma with BRAF mutations; Oral bioavailability = 95%; Elimination half-life = 8 h; Protein binding = 99.7%

Pharmacokinetics

Dabrafenib exhibits an oral bioavailability of 95%, indicative of extensive absorption and low firstpass intestinal and hepatic metabolism. The excellent oral bioavailability contributes to a much lower dosage than vemurafenib (150 mg, BID vs. 960 mg, BID). It has an elimination half-life of 8 h, resulting in twice-daily dosing regimen. Dabrafenib undergoes metabolism primarily via oxidation of the t-butyl group to form hydroxydabrafenib 6, which is further oxidized to carboxydabrafenib 7. Subsequent decarboxylation furnishes the desmethyl-dabrafenib 8 via a pH-dependent decarboxylation (Fig. 4). The major route of elimination of dabrafenib is a combination of oxidative metabolism (48% of the dose) and biliary excretion.

Clinical Use

Selective inhibitor of BRAF-kinase:
Treatment of metastatic melanoma and advanced non-small cell lung cancer with a BRAF V600 mutation

target

B-Raf (V600E)

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Oestrogens and progestogens: possibly reduced contraceptive effect.

Metabolism

Metabolism is mainly by CYP2C8 and CYP3A4 isoenzymes to form hydroxy-dabrafenib, which is further oxidised via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can be decarboxylated via a nonenzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolised by CYP3A4 to oxidative metabolites. Both hydroxyand desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib while the activity of carboxy-darafenib is not likely to be significant.

References

1) Huang?et al. (2013),?B-Raf and the inhibitors: from bench to bedside; J. Hematol. Oncol.,?6?1 2) Ji?et al. (2016),?Endoplasmic reticulum stress-induced autophagy determines the susceptibility of melanoma cells to dabrafenib; Drugs Des. Dev. Ther.?10?2491 3) Herr?et al.?(2015),?B-Raf inhibitors induce epithelial differentiation in BRAF-mutant colorectal cancer cells; Cancer Res.,?75?216

Dabrafenib Preparation Products And Raw materials

Raw materials

Preparation Products

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Dabrafenib Suppliers

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View Lastest Price from Dabrafenib manufacturers

Zison Pharmaceutical (Shandong) Co., Ltd.
Product
Dabrafenib free base 1195765-45-7
Price
US $0.00/kg
Min. Order
0.1kg
Purity
99.9%
Supply Ability
40-50kgs
Release date
2024-05-24
Zibo Hangyu Biotechnology Development Co., Ltd
Product
Dabrafenib 1195765-45-7
Price
US $70.00-700.00/kg
Min. Order
10kg
Purity
0.99
Supply Ability
20tons
Release date
2023-10-30
Henan Bao Enluo International TradeCo.，LTD
Product
Dabrafenib 1195765-45-7
Price
US $100.00/kg
Min. Order
1kg
Purity
99%
Supply Ability
1000tons
Release date
2023-07-20

1195765-45-7, DabrafenibRelated Search:

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  • Dabrafenib
  • N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
  • Dabrafenib free base(GSK2118436A)
  • Dabrafenib (GSK2118436)
  • GSK2118436A
  • Dabrafenib (GSK2118436A)
  • CS-658
  • N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
  • Dabrafenib KB-57246
  • Debrafenib API
  • BenzenesulfonaMide, N-[3-[5-(2-aMino-4-pyriMidinyl)-2-(1,1-diMethylethyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluoro-
  • N-(3-(5-(2-aminopyrimidin-4-yl)-2-tert-butylthiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide
  • Dabrafenib N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide
  • N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide Dabrafenib
  • Dabrafenib Base
  • Dabrafenib(GSK2118436) KB-57246
  • Dabrafenib, >=98%
  • GSK2118436, Dabrafenib, GSK2118436A
  • Dabrafenib(free base)
  • Debrafenib free base
  • N-(3-(5-(2-Aminopyrimidin-4-yl)-2-tert-butylthiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenes
  • Dabrafenib, 98%, a mutant BRAFV600 specific inhibitor
  • GSK2118436A (Dabrafenib)
  • GSK2118436A (DABRAFENIB);GSK-2118436B (DABRAFENIB MESYLATE);GSK-2118436A;GSK-2118436;GSK2118436A;GSK2118436A;GSK 2118436;GSK 2118436
  • GSK-2118436B (Dabrafenib Mesylate)
  • Dabrafenib USP/EP/BP
  • n-(3-(5-(2-amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl)-...
  • Darla fini
  • Dapafenib impurities
  • GSK-2118436,inhibit,GSK 2118436,Dabrafenib,Raf kinases,Inhibitor,Raf
  • abrafenib
  • N-[3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluoro-benzenesulfonamide
  • 1195765-45-7
  • 115765-45-7
  • C23H20F3N5O2S2
  • Inhibitors
  • inhibitor
  • MAPK
  • API
  • API
  • Raf B protein kinase inhibitor
  • 1195765-45-7