ArticleScientific reports2017
An engineered protein antagonist of K-Ras/B-Raf interaction.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 65 citations in OpenAlex.
- Precision Targeting ofInternational journal of molecular sciences · 2026Review
- Inducible tag-free degradation of endogenous proteins with AlissAID and development of a photoactivable inducer.Communications biology · 2025Article
- A Hit Prioritization Strategy for Compound Library Screening Using LiP-MS and Molecular Dynamics Simulations Applied to KRas G12D Inhibitors.Analytical chemistry · 2025Article
- Motif-guided identification of KRAS-interacting proteins.BMC biology · 2024Article
- Facile Access to Branched Multispecific Proteins.Bioconjugate chemistry · 2024Article
- An engineering strategy to target activated EGFR with CAR T cells.Cell reports methods · 2024Article
- Multiplexed imaging for probing RAS-RAF interactions in living cells.Biochimica et biophysica acta. Biomembranes · 2023Article
- Targeting Ras with protein engineering.Oncotarget · 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
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- KRAS Inhibitor that Simultaneously Inhibits Nucleotide Exchange Activity and Effector Engagement.ACS bio & med chem Au · 2022Article
- 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
- RAS-Driven Macropinocytosis of Albumin or Dextran Reveals Mutation-Specific Target Engagement of RAS p.G12C Inhibitor ARS-1620 by NIR-Fluorescence Imaging.Molecular imaging and biology · 2022Article
- Engineering Strategies to Overcome the Stability-Function Trade-Off in Proteins.ACS synthetic biology · 2022Review
- Evaluation of docking procedures reliability in affitins-partners interactions.Frontiers in chemistry · 2022Article
- Targeting the "undruggable" RAS with biologics.Advances in cancer research · 2022Review
- Affinity and Stability Analysis of Yeast Displayed Proteins.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Generation of Thermally Stable Affinity Pairs for Sensitive, Specific Immunoassays.Methods in molecular biology (Clifton, N.J.) · 2022Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
Ras is at the hub of signal transduction pathways controlling cell proliferation and survival. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction. R11.1.6 directly blocks interaction with Raf and reduces signaling through the Raf/MEK/ERK pathway. Our results support greater consideration of the state of switch I and provide a novel tool to study Ras biology. Most importantly, this work makes an unprecedented contribution to Ras research in inhibitor development strategy by revealing details of a targetable binding surface. Unlike the polar interfaces found for Ras/effector interactions, the K-Ras/R11.1.6 complex reveals an extensive hydrophobic interface that can serve as a template to advance the development of high affinity, non-covalent inhibitors of K-Ras oncogenic mutants.
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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.