1. Specific inhibition of oncogenic RAS using cell-permeable RAS-binding domains.
- Author
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Nomura TK, Heishima K, Sugito N, Sugawara R, Ueda H, Yukihiro A, and Honda R
- Subjects
- Animals, Antineoplastic Agents chemistry, Binding Sites drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Drug Screening Assays, Antitumor, Female, Humans, Male, Mice, Mice, Inbred BALB C, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Signal Transduction drug effects, Tumor Cells, Cultured, ras Proteins genetics, Antineoplastic Agents pharmacology, ras Proteins antagonists & inhibitors
- Abstract
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 exerts anticancer activity against several KRAS-mutant cancer cell lines. Moreover, Pen-cRaf-v1 exhibits excellent activity comparable with a leading pan-RAS inhibitor (BI-2852), as well as high target specificity in transcriptome analysis and alanine mutation analysis. These findings demonstrate that specific inhibition of oncogenic RAS, and possibly treatment of RAS-mutant cancer, is feasible by intracellular delivery of RBD., Competing Interests: Declaration of interests R.H. and Y.A. are the authors of a pending patent on RAS inhibitors developed in this study. The other authors declare no potential conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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