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

Jia Lu, Rane A. Harrison, Lianbo Li, Mei Zeng, Sudershan Gondi, David Scott, Nathanael S. Gray, John R. Engen, Kenneth D. Westover

Research output: Contribution to journalArticle

14 Scopus citations

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. Covalent inhibitors are promising for addressing cancers driven by KRAS G12C, the most common KRAS mutation in lung cancer. Lu et al. characterize a quinazoline switch II pocket (SIIP) inhibitor and demonstrate the utility of HDX MS for characterizing SIIP compounds.

Original languageEnglish (US)
JournalStructure
DOIs
StateAccepted/In press - 2017

Keywords

  • Covalent inhibitor
  • Drug discovery
  • Protein dynamics
  • RAS

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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