Reference - Detail
| RRC ID | 78888 |
|---|---|
| Author | Nomura TK, Heishima K, Sugito N, Sugawara R, Ueda H, Yukihiro A, Honda R. |
| Title | Specific inhibition of oncogenic RAS using cell-permeable RAS-binding domains. |
| Journal | Cell Chem Biol |
| 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. |
| Volume | 28(11) |
| Pages | 1581-1589.e6 |
| Published | 2021-11-18 |
| DOI | 10.1016/j.chembiol.2021.04.013 |
| PII | S2451-9456(21)00206-3 |
| PMID | 33964212 |
| MeSH | Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* 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 / antagonists & inhibitors* ras Proteins / genetics |
| IF | 6.762 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 26 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | HCT116(RCB2979) Colon-26(RCB2657) |