melanoma drug | Dabrafenib (Dabrafenib) is produced by GlaxoSmithKline (GSK) A drug developed for the treatment of metastatic melanoma is a BRAF inhibitor cancer drug, which is used in the form of mesylate. The former name is GSK2118436, and the trade name is Tafinlar. on 29-application for marketing. Tafinlar is approved for the treatment of unresectable melanomas (tumors that cannot be surgically removed) and metastatic melanomas (tumors that have spread to other organs in the body) carrying the BRAF V600E mutation, it cannot be used to treat wild-type BRAF melanoma. Mekinist is used to treat unresectable or metastatic melanoma with BRAF V600E or V600K mutations, and Mekinist should not be used to treat melanoma patients who have previously used BRAF inhibitors. The combination of these two drugs is considered to have a more effective and lasting therapeutic effect on melanoma, and the combination of the two drugs is also considered to be the main commercial opportunity for the two drugs. |
synthesis method | The key step in the synthesis of Dabrafenib is the construction of 1, 3-thiazole ring, it is generally derived from direct cyclization of thioamides as 1,3-nucleophiles and α-carbonyl halides as 1,2-amphiphilic reagents. Sulfonyl chloride 1 and aniline 2 gave sulfonamide 3 under basic conditions. Methylpyrimidine 4 with non-nucleophilic strong base LiHMDS to remove the acidic proton on the methyl group after reaction with 3 to obtain 5, the latter with NBS alpha-bromination to obtain 1,2-amphiphilic reagent 6,6 is further reacted with 1,3-amphiphilic nucleophile 7 to obtain ring closure 8, and then reacted with ammonia water to obtain Dabrafenib. FIG. 1 shows the synthetic scheme of Dabrafenib. |
biological activity | Dabrafenib (GSK2118436) is a mutant BRAFV600 specific inhibitor with an IC50 of 0.8 nM, the B- Raf(wt) and c-Raf effects were 4 and 6 times lower. Dabrafenib (GSK2118436, GSK2118436A) is a mutant BRAFV600 specific inhibitor with an IC50 of 0.7 nM in a cell-free assay, acting on B- Raf(wt). And c-Raf effect were 7 and 9 times lower, respectively. |
Target | Value |
B-Raf (V600E)
(Cell-free assay)
| 0.7 nM |
B-Raf
(Cell-free assay)
| 5.2 nM |
C-Raf
(Cell-free assay)
| 6.3 nM |