Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions

Christine Huynh; Jasper Dingemanse; Henriette E Meyer Zu Schwabedissen; Patricia N Sidharta

doi:10.1016/j.phrs.2020.105092

Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions

Pharmacol Res. 2020 Nov:161:105092. doi: 10.1016/j.phrs.2020.105092. Epub 2020 Aug 3.

Authors

Christine Huynh¹, Jasper Dingemanse², Henriette E Meyer Zu Schwabedissen³, Patricia N Sidharta⁴

Affiliations

¹ Idorsia Pharmaceuticals Ltd, Department of Clinical Pharmacology, Hegenheimermattweg 91, 4123 Allschwil, Switzerland; Biopharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
² Idorsia Pharmaceuticals Ltd, Department of Clinical Pharmacology, Hegenheimermattweg 91, 4123 Allschwil, Switzerland.
³ Biopharmacy, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056, Basel, Switzerland.
⁴ Idorsia Pharmaceuticals Ltd, Department of Clinical Pharmacology, Hegenheimermattweg 91, 4123 Allschwil, Switzerland. Electronic address: patricia.sidharta@idorsia.com.

PMID: 32758634
DOI: 10.1016/j.phrs.2020.105092

Abstract

The impact of the C-X-C receptor (CXCR) 7 and its close co-player CXCR4 in different physiological and pathophysiological processes has been extensively investigated within the last decades. Following activation by their shared ligand C-X-C ligand (CXCL) 12, both chemokine receptors can induce various routes of cell signaling and/or scavenge CXCL12 from the extracellular environment. This contributes to organ development and maintenance of homeostasis. Alterations of the CXCR4/CXCR7-CXCL12 axis have been detected in diseases such as cancer, central nervous system and cardiac disorders, and autoimmune diseases. These alterations include changes of the expression pattern, distribution, or downstream effects. The progression of the diseases can be regulated in preclinical models by the use of various modulators suggesting that this axis serves as a promising therapeutic target. It is therefore of great interest to investigate CXCR4/CXCR7/CXCL12 modulators in clinical development, with several CXCR4 and CXCL12 modulators such as plerixafor, ulocuplumab, balixafortide, and olaptesed pegol having already reached this stage. An overview is presented of the most important diseases whose outcomes can be positively or negatively regulated by the CXCR4/CXCR7-CXCL12 axis and summarizes preclinical and clinical data of modulators of that axis. Contrary to CXCR4 and CXCL12 modulators, CXCR7 modulators have, thus far, not been extensively studied. Therefore, more (pre)clinical investigations are needed.

Keywords: Balixafortide (PubChem CID: 138752609); Chemokine; Decursin (PubChem CID: 442126); Doxorubicin (PubChem CID: 31703); Enzalutamide (PubChem CID: 15951529); Glioblastoma; LY2510924 (PubChem CID: 129010506); Mafosfamid (PubChem CID: 104746); Motixafortide (PubChem CID: 91865076); Multiple sclerosis; Myocardial infarction; Olaptesed pegol (PubChem CID: 86278354); Plerixafor (PubChem CID: 65015); Prostate carcinoma; Renal cell carcinoma; Ulocuplumab (PubChem SID: 381127169).

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents / therapeutic use
Central Nervous System Agents / therapeutic use
Central Nervous System Diseases / drug therapy
Central Nervous System Diseases / metabolism*
Central Nervous System Diseases / pathology
Central Nervous System Diseases / physiopathology
Chemokine CXCL12 / metabolism*
Humans
Molecular Targeted Therapy
Neoplasms / drug therapy
Neoplasms / metabolism*
Neoplasms / pathology
Neoplasms / physiopathology
Receptors, CXCR / metabolism*
Receptors, CXCR4 / metabolism*
Signal Transduction

Substances

ACKR3 protein, human
Antineoplastic Agents
CXCL12 protein, human
CXCR4 protein, human
Central Nervous System Agents
Chemokine CXCL12
Receptors, CXCR
Receptors, CXCR4