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Specific inhibition of oncogenic RAS using cell-permeable RAS-binding domains

Cell Chem Biol. 2021-05; 
Teiko Komori Nomura, Kazuki Heishima, Nobuhiko Sugito, Ryota Sugawara, Hiroshi Ueda, Akao Yukihiro, Ryo Honda
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Endotoxin Detection & Removal System … of protein, as judged by ToxinSensor Chromogenic LAL Endotoxin Assay Kit (GenScript #L00350C). Prior to use, the protein was reconstituted by adding deionized water and passed … Get A Quote

摘要

Oncogenic RAS proteins, common oncogenic drivers in many human cancers, have been refractory to conventional small-molecule and macromolecule inhibitors due to their intracellular localization and the lack of druggable pockets. Here, we present a feasible strategy for designing RAS inhibitors that involves intracellular delivery of RAS-binding domain (RBD), a nanomolar-affinity specific ligand of RAS. Screening of 51 different combinations of RBD and cell-permeable peptides has identified Pen-cRaf-v1 as a cell-permeable pan-RAS inhibitor capable of targeting both G12C and non-G12C RAS mutants. Pen-cRaf-v1 crosses the cell membrane via endocytosis, competitively inhibits RAS-effector interaction, and thereby exe... More

關鍵詞

RAS, RAS-binding domain, cell-permeable peptides, fusion protein, molecular-targeted therapy, oncology, protein transduction, protein-protein interaction inhibitor, undruggable target
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