ArticleThe Journal of biological chemistry2018
Exceptionally high-affinity Ras binders that remodel its effector domain.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Mechanistic insights on spatiotemporal control of Ras-signaling.Biological chemistry · 2026Review
- Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges.Signal transduction and targeted therapy · 2025Review
- From Concepts to Inhibitors: A Blueprint for Targeting Protein-Protein Interactions.Chemical reviews · 2025Review
- Motif-guided identification of KRAS-interacting proteins.BMC biology · 2024Article
- Therapeutic developments in pancreatic cancer.Nature reviews. Gastroenterology & hepatology · 2024Review
- Article
- RAS degraders: The new frontier for RAS-driven cancers.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS.Signal transduction and targeted therapy · 2023Review
- Eliminating oncogenic RAS: back to the future at the drawing board.Biochemical Society transactions · 2023Article
- Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).Nature chemical biology · 2022Article
- Inhibition of RAS-driven signaling and tumorigenesis with a pan-RAS monobody targeting the Switch I/II pocket.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- The current state of the art and future trends in RAS-targeted cancer therapies.Nature reviews. Clinical oncology · 2022Review
- Targeting the "undruggable" RAS with biologics.Advances in cancer research · 2022Review
- Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling.Chemical science · 2021Article
- The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells.Frontiers in molecular biosciences · 2021Article
- NMR in integrated biophysical drug discovery for RAS: past, present, and future.Journal of biomolecular NMR · 2020Review
- GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf.ACS central science · 2020Article
- Conformation-specific inhibitors of activated Ras GTPases reveal limited Ras dependency of patient-derived cancer organoids.The Journal of biological chemistry · 2020Article
- Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant-driven tumor growth.Science advances · 2020Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Ras proteins are aberrantly activated in a wide range of human cancers, often endowing tumors with aggressive properties and resistance to therapy. Decades of effort to develop direct Ras inhibitors for clinical use have thus far failed, largely because of a lack of adequate small-molecule-binding pockets on the Ras surface. Here, we report the discovery of Ras-binding miniproteins from a naïve library and their evolution to afford versions with midpicomolar affinity to Ras. A series of biochemical experiments indicated that these miniproteins bind to the Ras effector domain as dimers, and high-resolution crystal structures revealed that these miniprotein dimers bind Ras in an unprecedented mode in which the Ras effector domain is remodeled to expose an extended pocket that connects two isolated pockets previously found to engage small-molecule ligands. We also report a Ras point mutant that stabilizes the protein in the open conformation trapped by these miniproteins. These findings provide new tools for studying Ras structure and function and present opportunities for the development of both miniprotein and small-molecule inhibitors that directly target the Ras proteins.
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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.