期刊
CELL CHEMICAL BIOLOGY
卷 28, 期 11, 页码 1581-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2021.04.013
关键词
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资金
- JSPS KAKENHI [19K16828]
- Hitachi Global Foundation
- Yasuda Medical Foundation
- Tokai Industry and Technology Foundation
- Chubu Regional Consortium for Advanced Medicine
- Department of Advanced Medicine, Nagoya University Hospital [A123]
- Grants-in-Aid for Scientific Research [19K16828] Funding Source: KAKEN
A new strategy for designing RAS inhibitors through intracellular delivery of RBD has been proposed, demonstrating specific inhibition of oncogenic RAS. The cell-permeable pan-RAS inhibitor Pen-cRaf-v1 effectively targets various RAS mutants and exhibits comparable anticancer activity to a leading pan-RAS inhibitor. This study highlights the feasibility of treating RAS-mutant cancers by targeting oncogenic RAS through intracellular delivery of RBD.
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.
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