ArticleThe Journal of biological chemistry2020
Conformation-specific inhibitors of activated Ras GTPases reveal limited Ras dependency of patient-derived cancer organoids.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 16 citations in OpenAlex.
- A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology.Nature chemical biology · 2026Article
- Thermal Stability, Plasma Pharmacokinetics, and Tumor Response Modeling of a Cell-Penetrating Protein That Cleaves RAS Family GTPases.ACS pharmacology & translational science · 2026Article
- Intracellular Delivery of Peptides and Proteins with an Engineered Membrane Translocation Domain.ACS chemical biology · 2026Article
- Intracellular Delivery of Peptides and Proteins with an Engineered Membrane Translocation Domain.bioRxiv : the preprint server for biology · 2026Article
- A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.Molecular oncology · 2025Article
- Targeting Ras with protein engineering.Oncotarget · 2023Review
- Eliminating oncogenic RAS: back to the future at the drawing board.Biochemical Society transactions · 2023Article
- Generation of Proteins with Free N-Terminal Cysteine by Aminopeptidases.Journal of the American Chemical Society · 2022Article
- Fluorescent Biosensor for Measuring Ras Activity in Living Cells.Journal of the American Chemical Society · 2022Article
- Engineered variants of the Ras effector protein RASSF5 (NORE1A) promote anticancer activities in lung adenocarcinoma.The Journal of biological chemistry · 2021Article
- EGFR-RAS-MAPK signaling is confined to the plasma membrane and associated endorecycling protrusions.The Journal of cell biology · 2021Article
- Discovery of a Bicyclic Peptidyl Pan-Ras Inhibitor.Journal of medicinal chemistry · 2021Article
- Disrupting the LC3 Interaction Region (LIR) Binding of Selective Autophagy Receptors Sensitizes AML Cell Lines to Cytarabine.Frontiers in cell and developmental biology · 2020Article
- Aloperine Exerts Antitumor Effects on Bladder Cancer in vitro.OncoTargets and therapy · 2020Article
- Molecular basis for Ras suppressor-1 binding to PINCH-1 in focal adhesion assembly.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 4 countries.
Funding
Abstract
The small GTPases H, K, and NRAS are molecular switches indispensable for proper regulation of cellular proliferation and growth. Several mutations in the genes encoding members of this protein family are associated with cancer and result in aberrant activation of signaling processes caused by a deregulated recruitment of downstream effector proteins. In this study, we engineered variants of the Ras-binding domain (RBD) of the C-Raf proto-oncogene, Ser/Thr kinase (CRAF). These variants bound with high affinity with the effector-binding site of Ras in an active conformation. Structural characterization disclosed how the newly identified RBD mutations cooperate and thereby enhance affinity with the effector-binding site in Ras compared with WT RBD. The engineered RBD variants closely mimicked the interaction mode of naturally occurring Ras effectors and acted as dominant-negative affinity reagents that block Ras signal transduction. Experiments with cancer cells showed that expression of these RBD variants inhibits Ras signaling, reducing cell growth and inducing apoptosis. Using these optimized RBD variants, we stratified patient-derived colorectal cancer organoids with known Ras mutational status according to their response to Ras inhibition. These results revealed that the presence of Ras mutations was insufficient to predict sensitivity to Ras inhibition, suggesting that not all of these tumors required Ras signaling for proliferation. In summary, by engineering the Ras/Raf interface of the CRAF-RBD, we identified potent and selective inhibitors of Ras in its active conformation that outcompete binding of Ras-signaling effectors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.