ArticleACS omega2020
PDE6D Inhibitors with a New Design Principle Selectively Block K-Ras Activity.
Article in ACS omega, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 46 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
- Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase 1 Inhibitors for Targeting Mevalonate Metabolism in Cancer.Journal of the American Chemical Society · 2026Article
- Covalent modification of a glutamic acid inspired by HaloTag technology.Nature communications · 2026Article
- Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling.Journal of medicinal chemistry · 2026Article
- Article
- Proteomics- and BRET- screens identify SPRY2 as a Ras effector that impacts its membrane organization.iScience · 2025Article
- Development of a Genetically Encoded and Potent PDE6D Inhibitor.Chembiochem : a European journal of chemical biology · 2025Article
- Drugging Ras trafficking-are there new roads to travel?npj drug discovery · 2025Review
- An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review.Molecular diversity · 2024Review
- KRas4b-Calmodulin Interaction with Membrane Surfaces: Role of Headgroup, Acyl Chain, and Electrostatics.Biochemistry · 2024Article
- Natural Product Graveoline Modulates Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Membrane Association: Insights from Advanced Spectroscopic Studies.ACS pharmacology & translational science · 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
- Antineoplastic effect of compounds C14 and P8 on TNBC and radioresistant TNBC cells by stabilizing the K-Ras4BFrontiers in oncology · 2024Article
- Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.Signal transduction and targeted therapy · 2023Review
- K-Ras Binds Calmodulin-Related Centrin1 with Potential Implications for K-Ras Driven Cancer Cell Stemness.Cancers · 2023Article
- Development of PD3 and PD3-B for PDEδ inhibition to modulate KRAS activity.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Structural and biophysical properties of farnesylated KRas interacting with the chaperone SmgGDS-558.Biophysical journal · 2022Article
- Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome.Nature structural & molecular biology · 2022Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
Abstract
The trafficking chaperone PDE6D (also referred to as PDEδ) has been nominated as a surrogate target for K-Ras4B (hereafter K-Ras). Arl2-assisted unloading of K-Ras from PDE6D in the perinuclear area is significant for correct K-Ras localization and therefore activity. However, the unloading mechanism also leads to the undesired ejection of PDE6D inhibitors. To counteract ejection, others have recently optimized inhibitors for picomolar affinities; however, cell penetration generally seems to remain an issue. To increase resilience against ejection, we engineered a "chemical spring" into prenyl-binding pocket inhibitors of PDE6D. Furthermore, cell penetration was improved by attaching a cell-penetration group, allowing us to arrive at micromolar in cellulo potencies in the first generation. Our model compounds, Deltaflexin-1 and -2, selectively disrupt K-Ras, but not H-Ras membrane organization. This selectivity profile is reflected in the antiproliferative activity on colorectal and breast cancer cells, as well as the ability to block stemness traits of lung and breast cancer cells. While our current model compounds still have a low in vitro potency, we expect that our modular and simple inhibitor redesign could significantly advance the development of pharmacologically more potent compounds against PDE6D and related targets, such as UNC119 in the future.
Identifiers
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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.