5FD2

B-Raf wild-type kinase domain in complex with a purinylpyridinylamino-based inhibitor

Summary for 5FD2

• Entry DOI: 10.2210/pdb5fd2/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, 6-[2-[[3-(dimethylsulfamoylamino)-2,6-bis(fluoranyl)phenyl]amino]pyridin-3-yl]-7~{H}-purine (3 entities in total)
• Functional Keywords: phosphotransferase, inhibitor, melanoma, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P15056
• Total number of polymer chains: 2
• Total formula weight: 69944.66

Authors

Whittington, D.A.,Epstein, L.F. (deposition date: 2015-12-15, release date: 2016-05-04, Last modification date: 2024-03-06)

Primary citation

Liu, L.,Lee, M.R.,Kim, J.L.,Whittington, D.A.,Bregman, H.,Hua, Z.,Lewis, R.T.,Martin, M.W.,Nishimura, N.,Potashman, M.,Yang, K.,Yi, S.,Vaida, K.R.,Epstein, L.F.,Babij, C.,Fernando, M.,Carnahan, J.,Norman, M.H.
Purinylpyridinylamino-based DFG-in/ alpha C-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.
Bioorg.Med.Chem., 24:2215-2234, 2016

PubMed 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 sulfamides 4-6) 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.

PubMed: 27085672
DOI: 10.1016/j.bmc.2016.03.055

Experimental method

X-RAY DIFFRACTION (2.89 Å)