Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling. Issue 10 (15th May 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 10(2016)
• Page Start: 2215
• Page End: 2234
• Publication Date: 2016-05-15
• Subjects: B-Raf -- Inhibitor -- DFG -- C-helix -- Selectivity -- v600e -- Wild-type -- Sulfonamide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.03.055
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: One of the challenges for targeting B-Raf V600E with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf WT, 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-Raf V600E . To explore this hypothesis, we transformed Type IIA inhibitor (1 ) into a series of Type IIB inhibitors (sulfonamides and sulfamides4 –6 ) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf V600E /B-Raf WT biochemical ( b S), cellular ( c S) selectivity, and the phospho-ERK activation ( p A). 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-Raf V600E selectivity.