Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling

Abstract One of the challenges for targeting B-Raf V600Ewith 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 TypeIIA 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 sulfamidesshow 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 V600Eselectivity.