Format

Send to

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

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

Author information

1
Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA).
2
Department of Pharmacology, The Ohio State University, 5065 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210 (USA). Roger.Briesewitz@osumc.edu.
3
Department of Chemistry and Biochemistry, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210 (USA). pei.3@osu.edu.

Abstract

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

PMID:
25950772
PMCID:
PMC4591930
DOI:
10.1002/anie.201502763
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center