Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling
| Autor: | Zihao Hua, Michele Potashman, Carol Babij, Manory Fernando, Nobuko Nishimura, Josette Carnahan, Joseph L. Kim, Linda F. Epstein, Matthew R. Lee, Kevin Yang, Richard T. Lewis, Douglas A. Whittington, Longbin Liu, Karina R. Vaida, Howard Bregman, Shuyan Yi, Mark H. Norman, Matthew W. Martin |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Protein Conformation alpha-Helical Proto-Oncogene Proteins B-raf 0301 basic medicine Pyridines Clinical Biochemistry Compound profiling Mutant Pharmaceutical Science Crystallography X-Ray Biochemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Drug Discovery Humans Point Mutation Protein Kinase Inhibitors Molecular Biology Amination chemistry.chemical_classification Organic Chemistry Wild type Small molecule Sulfonamide 030104 developmental biology Monomer chemistry Purines Drug Design Helix Molecular Medicine Selectivity |
| Zdroj: | Bioorganic & Medicinal Chemistry. 24:2215-2234 |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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