KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry

Structure. 2017 Sep 5;25(9):1442-1448.e3. doi: 10.1016/j.str.2017.07.003. Epub 2017 Aug 3.

Abstract

KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basis for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP.

Keywords: RAS; covalent inhibitor; drug discovery; protein dynamics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Crystallography, X-Ray
  • Deuterium Exchange Measurement
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Conformation
  • Mutation*
  • Proto-Oncogene Proteins p21(ras) / chemistry*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • KRAS protein, human
  • Quinazolines
  • Proto-Oncogene Proteins p21(ras)