1269667-64-2Relevant academic research and scientific papers
Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling
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.
, p. 2215 - 2234 (2016/04/26)
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.
RAF INHIBITOR COMPOUNDS AND METHODS OF USE THEREOF
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, (2011/04/14)
Compounds of Formula I are useful for inhibition of Raf kinases. Methods of using compounds of Formula I and stereoisomers, tautomers, prodrugs and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or trea
