Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization

Autor: Sara M. Rankin, Viktorija Daugvilaite, Katia De Filippo, Goda Juzenaite, Astrid Sissel Jørgensen, Mette M. Rosenkilde, Maša Mavri, Christian Berg, Tau Benned-Jensen, Gertrud Malene Hjortø, Jon Våbenø
Přispěvatelé: Wellcome Trust
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Benzylamines
Receptor expression
PROTEIN
Medicine (miscellaneous)
Pharmacology
Cyclams
CXCR4
receptor pharmacology
Mice
Drug Delivery Systems
0302 clinical medicine
Receptor pharmacology
Chlorocebus aethiops
Granulocyte Colony-Stimulating Factor
udc:577
Biology (General)
Receptor
beta-Arrestins
Molecular medicine
SMALL-MOLECULE AGONISTS
Chemistry
Haematopoietic stem cells
Hematopoietic stem cell
CHEMOTAXIS
Hematopoietic Stem Cell Mobilization
GTP-binding proteins
medicine.anatomical_structure
Pharmaceutical Preparations
030220 oncology & carcinogenesis
CHEMOKINE RECEPTOR
COS Cells
Aminoquinolines
Female
General Agricultural and Biological Sciences
medicine.drug
CXCR4 RECEPTOR
BICYCLAM NONPEPTIDE ANTAGONISTS
Receptors
CXCR4
Receptors
CXCR3
QH301-705.5
FACTOR-I
INHIBITION
Butylamines
Article
General Biochemistry
Genetics and Molecular Biology
SDF-1
03 medical and health sciences
stem cells
In vivo
Cell Line
Tumor
medicine
Animals
Humans
TRAFFICKING
molecular medicine
Plerixafor
Hematopoietic Stem Cells
hematopoietic stem cells
Mice
Inbred C57BL
HEK293 Cells
030104 developmental biology
Benzimidazoles
Bone marrow
Zdroj: Communications Biology
Jorgensen, A S, Daugvilaite, V, De Filippo, K, Berg, C, Mavri, M, Benned-Jensen, T, Juzenaite, G, Hjorto, G, Rankin, S, Vabeno, J & Rosenkilde, M M 2021, ' Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization ', Communications Biology, vol. 4, no. 1, 569 . https://doi.org/10.1038/s42003-021-02070-9
Communications Biology, Vol 4, Iss 1, Pp 1-12 (2021)
Communications biology, vol. 4, no. 569, 2021.
ISSN: 2399-3642
DOI: 10.1038/s42003-021-02070-9
Popis: Following the FDA-approval of the hematopoietic stem cell (HSC) mobilizer plerixafor, orally available and potent CXCR4 antagonists were pursued. One such proposition was AMD11070, which was orally active and had superior antagonism in vitro; however, it did not appear as effective for HSC mobilization in vivo. Here we show that while AMD11070 acts as a full antagonist, plerixafor acts biased by stimulating β-arrestin recruitment while fully antagonizing G protein. Consequently, while AMD11070 prevents the constitutive receptor internalization, plerixafor allows it and thereby decreases receptor expression. These findings are confirmed by the successful transfer of both ligands’ binding sites and action to the related CXCR3 receptor. In vivo, plerixafor exhibits superior HSC mobilization associated with a dramatic reversal of the CXCL12 gradient across the bone marrow endothelium, which is not seen for AMD11070. We propose that the biased action of plerixafor is central for its superior therapeutic effect in HSC mobilization.
Jørgensen et al. investigate the effects of the CXCR4 targeting agents, AMD3100 (Plerixafor) and AMD11070, and show that AMD3100, unlike AMD11070, is biased with intrinsic β-arrestin recruitment agonism and full G protein antagonism. They finally propose that this biased action of AMD3100 is central for its superior therapeutic effect on mobilizing stem cells.
Databáze: OpenAIRE
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