ArticleAngewandte Chemie (International ed. in English)2022
A Chemical Biology Toolbox Targeting the Intracellular Binding Site of CCR9: Fluorescent Ligands, New Drug Leads and PROTACs.
Article in Angewandte Chemie (International ed. in English), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 69 citations in OpenAlex.
- Targeting tumor-associated G-protein coupled receptors: beyond single-axis inhibition toward multidimensional regulation.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Replacing Ecologically Risky Trifluoroacetic Acid and Acetonitrile With Methanesulfonic Acid and Dimethyl Carbonate in High-Performance Liquid Chromatography Analyses of Small Molecule Drugs.Journal of separation science · 2026Article
- Development and characterization of endolysosomal trafficking targeting chimera degraders of αJournal of advanced research · 2026Article
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
- Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation.Journal of the American Chemical Society · 2026Review
- Lymphocyte homing disorder: a concealed driver of intestinal immune collapse in sepsis.Frontiers in immunology · 2026Review
- Leveraging Targeted Protein Degradation for G Protein-Coupled Receptors: The Development of CCR2 Molecular Degraders.Journal of medicinal chemistry · 2025Article
- Elucidating biased signaling in class A GPCRs.Trends in pharmacological sciences · 2025Review
- Target Engagement Studies and Kinetic Live-Cell Degradation Assays Enable the Systematic Characterization of Histone Deacetylase 6 Degraders.ACS pharmacology & translational science · 2025Article
- Development of PROTAC-Based Strategies for Cannabinoid Receptor Type 1 (CBACS pharmacology & translational science · 2025Article
- Targeted protein degradation with small molecules for cancer immunotherapy.Asian journal of pharmaceutical sciences · 2025Review
- Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.Nature reviews. Drug discovery · 2025Review
- A Fluorescent Probe Enables the Discovery of Improved Antagonists Targeting the Intracellular Allosteric Site of the Chemokine Receptor CCR7.Journal of medicinal chemistry · 2025Article
- A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR.Nature communications · 2024Article
- Inducing Receptor Degradation as a Novel Approach to Target CC Chemokine Receptor 2 (CCR2).International journal of molecular sciences · 2024Article
- Fluorophore-Labeled Pyrrolones Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR1.ACS pharmacology & translational science · 2024Article
- Structural perspectives on chemokine receptors.Biochemical Society transactions · 2024Review
- Development of a Fluorescent Ligand for the Intracellular Allosteric Binding Site of the Neurotensin Receptor 1.ACS pharmacology & translational science · 2024Article
- Targeted degradation of extracellular secreted and membrane proteins.Trends in pharmacological sciences · 2023Review
- Cu-NHC Complex for Chan-Evans-Lam Cross-Coupling Reactions ofEuropean journal of organic chemistry · 2023Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A conserved intracellular allosteric binding site (IABS) has recently been identified at several G protein-coupled receptors (GPCRs). Starting from vercirnon, an intracellular C-C chemokine receptor type 9 (CCR9) antagonist and previous phase III clinical candidate for the treatment of Crohn's disease, we developed a chemical biology toolbox targeting the IABS of CCR9. We first synthesized a fluorescent ligand enabling equilibrium and kinetic binding studies via NanoBRET as well as fluorescence microscopy. Applying this molecular tool in a membrane-based setup and in living cells, we discovered a 4-aminopyrimidine analogue as a new intracellular CCR9 antagonist with improved affinity. To chemically induce CCR9 degradation, we then developed the first PROTAC targeting the IABS of GPCRs. In a proof-of-principle study, we succeeded in showing that our CCR9-PROTAC is able to reduce CCR9 levels, thereby offering an unprecedented approach to modulate GPCR activity.
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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.