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

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

  • Bioorg Med Chem. 2016 May 15;24(10):2215-34. doi: 10.1016/j.bmc.2016.03.055.
Longbin Liu 1,  Matthew R Lee 2,  Joseph L Kim 3,  Douglas A Whittington 3,  Howard Bregman 4,  Zihao Hua 4,  Richard T Lewis 4,  Matthew W Martin 4,  Nobuko Nishimura 5,  Michele Potashman 4,  Kevin Yang 5,  Shuyan Yi 4,  Karina R Vaida 4,  Linda F Epstein 3,  Carol Babij 6,  Manory Fernando 6,  Josette Carnahan 6,  Mark H Norman 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: lliu@amgen.com.
  • 2 Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
  • 3 Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
  • 4 Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
  • 5 Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
  • 6 Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
PMID: 27085672 DOI: 10.1016/j.bmc.2016.03.055
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.

Keywords

B-Raf; C-helix; DFG; Inhibitor; Selectivity; Sulfonamide; Wild-type; v600e.

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