Covalent guanosine mimetic inhibitors of G12C KRAS

Yuan Xiong, Jia Lu, John Hunter, Lianbo Li, David Scott, Hwan Geun Choi, Sang Min Lim, Anuj Manandhar, Sudershan Gondi, Taebo Sim, Kenneth D. Westover, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure−activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound 11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake. The SAR and crystallographic results reaffirm the exquisite molecular recognition that exists in the diphosphate region of RAS for guanosine nucleotides which must be considered in the design of nucleotide-competitive inhibitors.

Original languageEnglish (US)
Pages (from-to)61-66
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number1
StatePublished - Jan 12 2017


  • ActivX
  • Bioisostere
  • Bisphosphonate
  • CPM
  • Covalent inhibitor
  • Drug design
  • GDP mimetic
  • KRAS G12C

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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