کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1360334 | 981433 | 2010 | 13 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Application of a novel [3+2] cycloaddition reaction to prepare substituted imidazoles and their use in the design of potent DFG-out allosteric B-Raf inhibitors Application of a novel [3+2] cycloaddition reaction to prepare substituted imidazoles and their use in the design of potent DFG-out allosteric B-Raf inhibitors](/preview/png/1360334.png)
B-Raf protein kinase, which is a key signaling molecule in the RAS–RAF–MEK–ERK signaling pathway, plays an important role in many cancers. The B-Raf V600E mutation represents the most frequent oncogenic kinase mutation known and is responsible for increased kinase activity in approximately 7% of all human cancers, establishing B-Raf as an important therapeutic target for inhibition. Through the use of an iterative program that utilized a chemocentric approach and a rational structure based design, we have developed novel, potent, and specific DFG-out allosteric inhibitors of B-Raf kinase. Here, we present efficient and versatile chemistry that utilizes a key one pot, [3+2] cycloaddition reaction to obtain highly substituted imidazoles and their application in the design of allosteric B-Raf inhibitors. Inhibitors based on this scaffold display subnanomolar potency and a favorable kinase profile.
We report the de novo design of a potent series of imidazole based inhibitors of B-Raf V600E, a novel [3+2] cycloaddition route to obtain tri-substituted imidazoles, the biochemical evaluation of a series of analogues, and unique kinase inhibition profiles of three selected molecules.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 18, Issue 1, 1 January 2010, Pages 292–304