title: 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(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.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: lliu@amgen.com.
authors.forename: Longbin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kim
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Zihao
authors.initials: Z
authors.lastname: Hua
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lewis
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Potashman
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Karina R
authors.initials: KR
authors.lastname: Vaida
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors.forename: Linda F
authors.initials: LF
authors.lastname: Epstein
authors.affiliation: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Babij
authors.affiliation: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Manory
authors.initials: M
authors.lastname: Fernando
authors.affiliation: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Josette
authors.initials: J
authors.lastname: Carnahan
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000586:Amination; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D017354:Point Mutation; D000072756:Protein Conformation, alpha-Helical / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D011725:Pyridines; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf; C-helix; DFG; Inhibitor; Selectivity; Sulfonamide; Wild-type; v600e