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 melanoma
1,2. 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 Inhibitor
3,4. 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 therapy
5.
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
- https://www.caymanchem.com/product/16989
- https://en.wikipedia.org/wiki/Dabrafenib
- https://pubchem.ncbi.nlm.nih.gov/compound/Dabrafenib
- 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.
- 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 BRAF
V600E 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-BRAF
V600E kinase (IC
50=0.65 nM) compared to its potency against wild-type B-raf (IC
50=3.2 nM). It also inhibits other kinases (e.g., CRAF) and other mutant B-raf kinases (BRAF
V600E and BRAF
V600D) with enzyme IC
50s 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-Raf
V600E 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.
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
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
