Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C

Mei Zeng, Jia Lu, Lianbo Li, Frederic Feru, Chunshan Quan, Thomas W. Gero, Scott B. Ficarro, Yuan Xiong, Chiara Ambrogio, Raymond M. Paranal, Marco Catalano, Jay Shao, Kwok Kin Wong, Jarrod A. Marto, Eric S. Fischer, Pasi A. Jänne, David A. Scott, Kenneth D. Westover, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.

Original languageEnglish (US)
Pages (from-to)1005-1016.e3
JournalCell Chemical Biology
Issue number8
StatePublished - Aug 17 2017


  • KRAS
  • covalent inhibitor
  • drug discovery
  • protein dynamics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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