ArticleScience signaling2018
Biased antagonism of CXCR4 avoids antagonist tolerance.
Article in Science signaling, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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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.
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Who cites it
23 citing papers in PubMed, 42 citations in OpenAlex.
- CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization.Scientific reports · 2025Article
- Characterization of a CXCR4 antagonist TIQ-15 with dual tropic HIV entry inhibition properties.PLoS pathogens · 2024Article
- Autoantibodies Targeting G-Protein-Coupled Receptors: Pathogenetic, Clinical and Therapeutic Implications in Systemic Sclerosis.International journal of molecular sciences · 2024Review
- Molecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system.Nature communications · 2023Article
- Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.International journal of molecular sciences · 2023Review
- Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation.Frontiers in immunology · 2023Review
- Comparison of the Response to the CXCR4 Antagonist AMD3100 during the Development of Retinal Organoids Derived from ES Cells and Zebrafish Retina.International journal of molecular sciences · 2022Article
- Article
- Dual role for CXCL12 signaling in semilunar valve development.Cell reports · 2021Article
- CXCR4 engagement triggers CD47 internalization and antitumor immunization in a mouse model of mesothelioma.EMBO molecular medicine · 2021Article
- Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization.Communications biology · 2021Article
- At the Bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer.Journal of leukocyte biology · 2021Review
- Article
- Design and Generation of Self-Assembling Peptide Virus-like Particles with Intrinsic GPCR Inhibitory Activity.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Regulation of the thrombin/protease-activated receptor 1 axis by chemokine (CThe Journal of biological chemistry · 2020Article
- Chemokines and galectins form heterodimers to modulate inflammation.EMBO reports · 2020Article
- β-Arrestin1 and β-Arrestin2 Are Required to Support the Activity of the CXCL12/HMGB1 Heterocomplex on CXCR4.Frontiers in immunology · 2020Article
- Targeting CXCR4 in AML and ALL.Frontiers in oncology · 2020Review
- G protein-coupled receptors in acquired epilepsy: Druggability and translatability.Progress in neurobiology · 2019Review
- Chemokines in COPD: From Implication to Therapeutic Use.International journal of molecular sciences · 2019Review
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
Abstract
Repeated dosing of drugs targeting G protein-coupled receptors can stimulate antagonist tolerance, which reduces their efficacy; thus, strategies to avoid tolerance are needed. The efficacy of AMD3100, a competitive antagonist of the chemokine receptor CXCR4 that mobilizes leukemic blasts from the bone marrow into the blood to sensitize them to chemotherapy, is reduced after prolonged treatment. Tolerance to AMD3100 increases the abundance of CXCR4 on the surface of leukemic blasts, which promotes their rehoming to the bone marrow. AMD3100 inhibits both G protein signaling by CXCR4 and β-arrestin1/2-dependent receptor endocytosis. We demonstrated that biased antagonists of G protein-dependent chemotaxis but not β-arrestin1/2 recruitment and subsequent receptor endocytosis avoided tolerance. The peptide antagonist X4-2-6, which is derived from transmembrane helix 2 and extracellular loop 1 of CXCR4, limited chemotaxis and signaling but did not promote CXCR4 accumulation on the cell surface or cause tolerance. The activity of X4-2-6 was due to its distinct mechanism of inhibition of CXCR4. The peptide formed a ternary complex with the receptor and its ligand, the chemokine CXCL12. Within this complex, X4-2-6 released the portion of CXCL12 critical for receptor-mediated activation of G proteins but enabled the rest of the chemokine to recruit β-arrestins to the receptor. In contrast, AMD3100 displaced all components of the chemokine responsible for CXCR4 activation. We further identified a small molecule with similar biased antagonist properties to those of X4-2-6, which may provide a viable alternative to patients when antagonist tolerance prevents drugs from reaching efficacy.
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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.