ArticleJournal of medicinal chemistry2022
Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- K-Ras controls asymmetric cell divisions from the primary cilium.Cell death & disease · 2026Article
- Biochemical Mechanisms of Phosphodiesterase 6D Inhibition in K-Ras-Driven Cancers.Applied biochemistry and biotechnology · 2026Article
- α-Halothioamide warheads with enhanced cysteine reactivity and specificity for covalent protein labelling.Nature communications · 2026Article
- Sequence-Dependent Heterotypic Assemblies of Intrinsically Disordered Peptides.ChemistryEurope · 2026Article
- Novel GαGTP Sensors Reveal Endogenous and Subcellular G Protein Signaling Dynamics.bioRxiv : the preprint server for biology · 2026Article
- Computational identification and mechanistic characterization of natural product binders targeting the PDE6D prenyl binding tunnel.Scientific reports · 2026Article
- Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling.Journal of medicinal chemistry · 2026Article
- Development of a Genetically Encoded and Potent PDE6D Inhibitor.Chembiochem : a European journal of chemical biology · 2025Article
- Heterochiral and Heterotypic Self-Assembly of Intrinsically Disordered Peptides Confers Peptide Supercoils with Exceptional Proteolytic Stability.Journal of the American Chemical Society · 2025Article
- Drugging Ras trafficking-are there new roads to travel?npj drug discovery · 2025Review
- Context-Dependent Heterotypic Assemblies of Intrinsically Disordered Peptides.Journal of the American Chemical Society · 2025Article
- Differential Lipid Binding Specificities of RAP1A and RAP1B are Encoded by the Amino Acid Sequence of the Membrane Anchors.Journal of the American Chemical Society · 2024Article
- An Improved PDE6D Inhibitor Combines with Sildenafil To InhibitJournal of medicinal chemistry · 2024Article
- DFT and molecular simulation validation of the binding activity of PDEδ inhibitors for repression of oncogenic k-Ras.PloS one · 2024Article
- Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer.Life science alliance · 2023Article
- A model-informed method to retrieve intrinsic from apparent cooperativity and project cellular target occupancy for ternary complex-forming compounds.RSC chemical biology · 2023Article
- Selected Approaches to Disrupting Protein-Protein Interactions within the MAPK/RAS Pathway.International journal of molecular sciences · 2023Review
- Blocking the Farnesyl Pocket of PDEδ Reduces Rheb-Dependent mTORC1 Activation and Survival ofFrontiers in pharmacology · 2022Article
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 3 countries.
Funding
Abstract
RAS is a major anticancer drug target which requires membrane localization to activate downstream signal transduction. The direct inhibition of RAS has proven to be challenging. Here, we present a novel strategy for targeting RAS by stabilizing its interaction with the prenyl-binding protein PDE6D and disrupting its localization. Using rationally designed RAS point mutations, we were able to stabilize the RAS:PDE6D complex by increasing the affinity of RAS for PDE6D, which resulted in the redirection of RAS to the cytoplasm and the primary cilium and inhibition of oncogenic RAS/ERK signaling. We developed an SPR fragment screening and identified fragments that bind at the KRAS:PDE6D interface, as shown through cocrystal structures. Finally, we show that the stoichiometric ratios of KRAS:PDE6D vary in different cell lines, suggesting that the impact of this strategy might be cell-type-dependent. This study forms the foundation from which a potential anticancer small-molecule RAS:PDE6D complex stabilizer could be developed.
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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.