AI Article Synopsis
- The FDA approved plerixafor as a hematopoietic stem cell (HSC) mobilizer, leading to the exploration of oral CXCR4 antagonists like AMD11070.
- Although AMD11070 is a strong antagonist in lab tests, it is less effective in actual HSC mobilization compared to plerixafor.
- Plerixafor not only blocks the receptor but also encourages a process that reduces receptor levels, enhancing its effectiveness in mobilizing HSCs in vivo.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115334 | PMC |
| http://dx.doi.org/10.1038/s42003-021-02070-9 | DOI Listing |
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