ArticlePloS one2017
Inhibition of prenylated KRAS in a lipid environment.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Exploration of Cryptic Pockets Using Enhanced Sampling Along Normal Modes: A Case Study of KRASJournal of chemical information and modeling · 2024Article
- Article
- Antipsychotic phenothiazine drugs bind to KRAS in vitro.Journal of biomolecular NMR · 2021Article
- A regulatory role of membrane by direct modulation of the catalytic kinase domain.Small GTPases · 2021Review
- Approaches to inhibiting oncogenic K-Ras.Small GTPases · 2021Review
- NMR in integrated biophysical drug discovery for RAS: past, present, and future.Journal of biomolecular NMR · 2020Review
- Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Therapeutic targeting of RAS: New hope for drugging the "undruggable".Biochimica et biophysica acta. Molecular cell research · 2020Review
- Biology, pathology, and therapeutic targeting of RAS.Advances in cancer research · 2020Review
- Structural basis of a small molecule targeting RNA for a specific splicing correction.Nature chemical biology · 2019Article
- Probing the Conformational and Energy Landscapes of KRAS Membrane Orientation.The journal of physical chemistry. B · 2019Article
- The role of PS 18:0/18:1 in membrane function.Nature communications · 2019Review
- DUckCov: a Dynamic Undocking-Based Virtual Screening Protocol for Covalent Binders.ChemMedChem · 2019Article
- Quantitative biophysical analysis defines key components modulating recruitment of the GTPase KRAS to the plasma membrane.The Journal of biological chemistry · 2019Article
- Pharmacological targeting of RAS: Recent success with direct inhibitors.Pharmacological research · 2019Review
- Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures.Nature reviews. Chemistry · 2018Article
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Authors and funding
37 authors.
Funding
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Abstract
RAS mutations lead to a constitutively active oncogenic protein that signals through multiple effector pathways. In this chemical biology study, we describe a novel coupled biochemical assay that measures activation of the effector BRAF by prenylated KRASG12V in a lipid-dependent manner. Using this assay, we discovered compounds that block biochemical and cellular functions of KRASG12V with low single-digit micromolar potency. We characterized the structural basis for inhibition using NMR methods and showed that the compounds stabilized the inactive conformation of KRASG12V. Determination of the biophysical affinity of binding using biolayer interferometry demonstrated that the potency of inhibition matches the affinity of binding only when KRAS is in its native state, namely post-translationally modified and in a lipid environment. The assays we describe here provide a first-time alignment across biochemical, biophysical, and cellular KRAS assays through incorporation of key physiological factors regulating RAS biology, namely a negatively charged lipid environment and prenylation, into the in vitro assays. These assays and the ligands we discovered are valuable tools for further study of KRAS inhibition and drug discovery.
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