- Protein kinase inhibitor and its composition and use thereof
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The invention relates to compounds as shown in the general formula (I), pharmaceutical compositions containing the compounds, a method for treating diseases and disease symptoms related to abnormal activity of protein kinase by using the compounds, and medicinal use of the compounds.
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- Discovery of a highly specific and potent pan-RAF inhibitor
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We describe the structure-based design and synthesis of N-(2,6-difluorophenyl)-3-(9H-purin-6-yl)pyridine-2-amine derivatives as a selective pan-RAF kinase inhibitor. The synthesized compounds showed highly potent and specific inhibition of the BRAFV600E mutant cell line. Among them, N-(3-((3-(9H-purin-6-yl) pyridine-2-yl)amino)-2,4-difluorophenyl)furan-3-sulfonamide (4b) exhibited the most potent inhibitory activities against protein kinase enzymes BRAFV600E, BRAFWT, and CRAF (IC50 of 2, 2, and 1 nM, respectively) and a mutant cell line bearing a BRAFV600E mutation, A375P (GI50 of 7 nM).
- Hong, Sung Pyo,Lee, Younho,Choi, Nam Song,Nam, Ky-Youb,Ahn, Soon Kil
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p. 1632 - 1637
(2016/10/13)
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- Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling
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One of the challenges for targeting B-RafV600E with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-RafWT, as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-RafV600E. To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-RafV600E/B-RafWT biochemical (bS), cellular (cS) selectivity, and the phospho-ERK activation (pA). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-RafV600E selectivity.
- Liu, Longbin,Lee, Matthew R.,Kim, Joseph L.,Whittington, Douglas A.,Bregman, Howard,Hua, Zihao,Lewis, Richard T.,Martin, Matthew W.,Nishimura, Nobuko,Potashman, Michele,Yang, Kevin,Yi, Shuyan,Vaida, Karina R.,Epstein, Linda F.,Babij, Carol,Fernando, Manory,Carnahan, Josette,Norman, Mark H.
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p. 2215 - 2234
(2016/04/26)
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- KINASE MODULATING COMPOUNDS, COMPOSITIONS CONTAINING THE SAME AND USE THEREOF
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The invention provides a compound represented by formula (I) which may modulate a kinase, and a pharmaceutical composition thereof, as well as the method for preventing or treating a protein kinase mediated disease or condition.
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- NOVEL PURINYLPYRIDINYLAMINO-2,4-DIFLUOROPHENYL SULFONAMIDE DERIVATIVE, PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION WITH INHIBITORY ACTIVITY AGAINST RAF KINASE, CONTAINING SAME AS ACTIVE INGREDIENT
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A novel purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition with an inhibitory activity against Raf kinase, containing the same as an active ingredient are provided. The purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative of the present invention effectively regulates the activity of B-Raf kinase, and thus may be useful for preventing or treating cancers induced by the over-activation of Raf kinase, especially various melanoma, colorectal cancer, prostate cancer, thyroid cancer, ovarian cancer and the like.
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