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

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.

Neuronal chemokine concentration gradients mediate effects of embryonic ethanol exposure on ectopic hypocretin/orexin neurons and behavior in zebrafish

“…This may involve different molecular mechanisms including the inhibition of nuclear translocation of NFκB that reduces chemokine transcription as shown in retinal progenitor cell culture 55 and of other downstream chemokine signaling pathways associated with transcription and migration 56 . Interestingly, in contrast to the Cxcl12 gradient in mouse bone marrow endothelium reported to be reversed by AMD3100 57 , we find here in zebrafish brain that the posterior-to-anterior gradients of cxcl12a transcripts and internalized Cxcr4b receptors are still present after AMD3100 treatment as well as after ethanol exposure. Together, our results reported here with the AMD3100 antagonist provide strong evidence that these natural gradients play a direct role in the ethanol-induced increase in Hcrt neuron number and their anterior and ectopic location.…”

Targeting the CCL2–CCR2 axis for atheroprotection

“…Despite the promiscuity, targeting-specific signalling cascades may be possible. For example, the development of CCR2-biased or probe-dependent antagonists that selectively block a certain chemokine or signalling pathway, sparing interactions with alternate chemokine ligands, [125][126][127] might be a promising approach. However, whether going for a selective vs. a non-selective strategy requires a deeper understanding of the alternative pathways beyond the main ligand and receptor and their roles in atherosclerosis.…”

CXCR4 as a novel target in immunology: moving away from typical antagonists

“…Apart from the previously discussed compounds there are several compounds targeting CXCR4 which could be of interest. AMD070/AMD11070 has been reported to bind into the minor pocket of CXCR4 based on docking and mutational studies [ 40 , 41 ] and might be an interesting molecule to evaluate further. TG-0054 developed and screened for cell mobilization displayed an immune suppressive function in minipigs [ 42 ], however the authors of the paper proposed that the mobilization of stem cells is the cause of this effect.…”