| RRC ID |
78888
|
| 著者 |
Nomura TK, Heishima K, Sugito N, Sugawara R, Ueda H, Yukihiro A, Honda R.
|
| タイトル |
Specific inhibition of oncogenic RAS using cell-permeable RAS-binding domains.
|
| ジャーナル |
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.
|
| 巻・号 |
28(11)
|
| ページ |
1581-1589.e6
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
HCT116(RCB2979)
Colon-26(RCB2657) |
