ArticleJournal of the American Chemical Society2018
Small Molecule Inhibitors of the PCSK9·LDLR Interaction.
Article in Journal of the American Chemical Society, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
24 citing papers in PubMed, 65 citations in OpenAlex.
- Discovery of Novel PCSK9-LDLR PPI Inhibitors by a Structural Modification Approach.Drug development research · 2026Article
- Lipid metabolism as a central driver of immune remodeling and therapeutic vulnerability in metastatic colorectal cancer.Lipids in health and disease · 2026Review
- Lomitapide response in a cohort of patients with homozygous familial hypercholesterolemia and the potential influence of MTTP gene variants.Orphanet journal of rare diseases · 2025Article
- Insights into Binding Mechanisms of Potential Inhibitors Targeting PCSK9 Protein via Molecular Dynamics Simulation and Free Energy Calculation.Molecules (Basel, Switzerland) · 2025Article
- The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment.International journal of molecular sciences · 2024Review
- Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.Signal transduction and targeted therapy · 2024Review
- Computational Design, Synthesis, and Biological Evaluation of Diimidazole Analogues Endowed with Dual PCSK9/HMG-CoAR-Inhibiting Activity.Journal of medicinal chemistry · 2023Article
- Brazilin fromAdvances in pharmacological and pharmaceutical sciences · 2023Article
- Discovery and SAR analysis of phenylbenzo[d][1,3]dioxole-based proprotein convertase subtilisin/kexin type 9 inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- mRNA Display Reaches for the Clinic with New PCSK9 Inhibitor.ACS medicinal chemistry letters · 2022Article
- Small molecule peptidomimetic trypsin inhibitors: validation of an EKO binding mode, but with a twist.Organic & biomolecular chemistry · 2022Article
- Novel Target Study to Cure Cardiovascular Disease regarding Proprotein Converse Subtilisin/Kexin Type 9.BioMed research international · 2022Article
- Prenylated Flavonoid Glycosides with PCSK9 mRNA Expression Inhibitory Activity from the Aerial Parts ofMolecules (Basel, Switzerland) · 2021Article
- Piptides: New, Easily Accessible Chemotypes For Interactions With Biomolecules.Angewandte Chemie (International ed. in English) · 2021Article
- Query-guided protein-protein interaction inhibitor discovery.Chemical science · 2021Article
- Small molecules targeting the NEDD8·NAE protein-protein interaction.Chemical science · 2020Article
- From methylene bridged diindole to carbonyl linked benzimidazoleindole: Development of potent and metabolically stable PCSK9 modulators.European journal of medicinal chemistry · 2020Article
- Pseurotin A as a novel suppressor of hormone dependent breast cancer progression and recurrence by inhibiting PCSK9 secretion and interaction with LDL receptor.Pharmacological research · 2020Article
- A small-molecule inhibitor of PCSK9 transcription ameliorates atherosclerosis through the modulation of FoxO1/3 and HNF1α.EBioMedicine · 2020Article
- Discovery of 2,3'-diindolylmethanes as a novel class of PCSK9 modulators.Bioorganic & medicinal chemistry letters · 2019Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The protein-protein interaction between proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR) is a relatively new, and extremely important, validated therapeutic target for treatment and prevention of heart disease. Experts in the area agree that the first small molecules to disrupt PCSK9·LDLR would represent a milestone in this field, yet few credible leads have been reported. This paper describes how side-chain orientations in preferred conformations of carefully designed chemotypes were compared with LDLR side chains at the PCSK9·LDLR interface to find molecules that would mimic interface regions of LDLR. This approach is an example of the procedure called EKO (Exploring Key Orientations). The guiding hypothesis on which EKO is based is that good matches indicate the chemotypes bearing the same side chains as the protein at the sites of overlay have the potential to disrupt the parent protein-protein interaction. In the event, the EKO procedure and one round of combinatorial fragment-based virtual docking led to the discovery of seven compounds that bound PCSK9 (SPR and ELISA) and had a favorable outcome in a cellular assay (hepatocyte uptake of fluorescently labeled low-density lipoprotein particles) and increased the expression LDLR on hepatocytes in culture. Three promising hit compounds in this series had dissociation constants for PCSK9 binding in the 20-40 μM range, and one of these was modified with a photoaffinity label and shown to form a covalent conjugate with PCSK9 on photolysis.
Identifiers
What OpenQuestion holds
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.