Inhibition of Ras signaling by blocking Ras-effector interactions with cyclic peptides

Angew Chem Int Ed Engl. 2015 Jun 22;54(26):7602-6. doi: 10.1002/anie.201502763. Epub 2015 May 7.


Ras genes are frequently activated in human cancers, but the mutant Ras proteins remain largely "undruggable" through the conventional small-molecule approach owing to the absence of any obvious binding pockets on their surfaces. By screening a combinatorial peptide library, followed by structure-activity relationship (SAR) analysis, we discovered a family of cyclic peptides possessing both Ras-binding and cell-penetrating properties. These cell-permeable cyclic peptides inhibit Ras signaling by binding to Ras-GTP and blocking its interaction with downstream proteins and they induce apoptosis of cancer cells. Our results demonstrate the feasibility of developing cyclic peptides for the inhibition of intracellular protein-protein interactions and of direct Ras inhibitors as a novel class of anticancer agents.

Keywords: Ras signaling; cancer; cell-penetrating peptides; cyclic peptides; protein-protein interactions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Humans
  • Molecular Structure
  • Peptides, Cyclic / metabolism*
  • Protein Binding
  • Structure-Activity Relationship
  • ras Proteins / metabolism*


  • Peptides, Cyclic
  • ras Proteins