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
CS-658;Dabrafenib;GSK2118436A;Debrafenib API;Dabrafenib Base;Dabrafenib, >=98%;Dabrafenib KB-57246;Debrafenib free base;Dabrafenib USP/EP/BP;Dabrafenib(free base)
CBNumber
CB32604230
Molecular Formula
C23H20F3N5O2S2
Formula Weight
519.56
MOL File
1195765-45-7.mol
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Dabrafenib Property

Boiling point:
653.7±65.0 °C(Predicted)
Density 
1.443
form 
White solid.
pka
6.62±0.10(Predicted)
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Safety

HS Code 
29350090
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Hazard and Precautionary Statements (GHS)

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N-Bromosuccinimide Price

Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
5mg
Price
$35
Updated
2021/03/22
Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
10mg
Price
$67
Updated
2021/03/22
Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
25mg
Price
$158
Updated
2021/03/22
Cayman Chemical
Product number
16989
Product name
Dabrafenib
Purity
≥98%
Packaging
50mg
Price
$263
Updated
2021/03/22
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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)

Definition

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

brand name

Tafinlar

Dabrafenib Preparation Products And Raw materials

Raw materials

Preparation Products

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Dabrafenib Suppliers

EASON Chemical Co., LIMITED
Tel
0576-89232655
Fax
0576-88860891
Email
info@seasonsbio.com
Country
China
ProdList
27
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58
Artis Biotech Co. Ltd.
Tel
Fax
0575-89298961
Email
sales@artis-standards.com
Country
China
ProdList
2261
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58
Shenzhen HwaGen Pharmaceutical Co.,Ltd
Tel
18927334162;18927339850
Fax
0752-5319394
Email
sales1@rafflespt.com
Country
China
ProdList
141
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58
Shanghai Drjart Biological Co., Ltd.
Tel
Email
tianxiao549423850@163.com
Country
China
ProdList
122
Advantage
58
Changzhou Yongfeng Biomedicine Co. Ltd.
Email
2973592490@qq.com
Country
China
ProdList
280
Advantage
58
Ningbo Risheng Pharmaceutical Technology Co., Ltd.
Tel
Fax
0574-89132888
Email
2928184953@qq.com
Country
China
ProdList
47
Advantage
58
Hubei Junxian Biotechnology Co., Ltd
Email
3464928989@qq.com
Country
China
ProdList
46
Advantage
58
Wuhan Sunrise Technology Development Co., Ltd.
Tel
027-83314682
Fax
+86 (27) 8331-4682
Email
whsrtech@vip.163.com;whsrtech@vip.163.com
Country
China
ProdList
280
Advantage
62
Shanghai Boyle Chemical Co., Ltd.
Fax
86-21-57758967
Email
sales@boylechem.com
Country
China
ProdList
2926
Advantage
55
Chembest Research Laboratories Limited
Tel
021-20908456-
Fax
021-58180499
Email
sales@BioChemBest.com
Country
China
ProdList
5948
Advantage
61
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View Lastest Price from Dabrafenib manufacturers

Hebei Lingding Biological Technology Co., Ltd
Product
Dabrafenib 1195765-45-7
Price
US $95.00-79.00/KG
Min. Order
1KG
Purity
99%
Supply Ability
9000kg/per week
Release date
2021-08-23
Zhuozhou Wenxi import and Export Co., Ltd
Product
Dabrafenib 1195765-45-7
Price
US $15.00-10.00/KG
Min. Order
1KG
Purity
99%+ HPLC
Supply Ability
Monthly supply of 1 ton
Release date
2021-07-11
Zhuozhou Wenxi import and Export Co., Ltd
Product
Dabrafenib 1195765-45-7
Price
US $15.00-10.00/KG
Min. Order
1KG
Purity
99%+ HPLC
Supply Ability
Monthly supply of 1 ton
Release date
2021-07-09

1195765-45-7, DabrafenibRelated Search:


  • 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
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  • 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
  • 1195765-45-7
  • 115765-45-7
  • C23H20F3N5O2S2
  • Inhibitors
  • inhibitor
  • MAPK
  • API
  • API
  • Raf B protein kinase inhibitor