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Inhibition of Ras Signaling by Blocking Ras–Effector Interactions with Cyclic Peptides
Author(s) -
Upadhyaya Punit,
Qian Ziqing,
Selner Nicholas G.,
Clippinger Sarah R.,
Wu Zhengrong,
Briesewitz Roger,
Pei Dehua
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201502763
Subject(s) - effector , cyclic peptide , intracellular , chemistry , microbiology and biotechnology , peptide , signal transduction , mutant , small molecule , protein–protein interaction , biochemistry , biology , gene
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.