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

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.

SUBMITTER: Upadhyaya P 

PROVIDER: S-EPMC4591930 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Upadhyaya Punit P   Qian Ziqing Z   Selner Nicholas G NG   Clippinger Sarah R SR   Wu Zhengrong Z   Briesewitz Roger R   Pei Dehua D  

Angewandte Chemie (International ed. in English) 20150507 26

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  ...[more]