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.
Idorsia Pharmaceuticals Ltd, Department of Clinical Pharmacology, Hegenheimermattweg 91, 4123 Allschwil, Switzerland.
Pharmacol Res. 2020 Nov;161:105092. doi: 10.1016/j.phrs.2020.105092. Epub 2020 Aug 3.
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.
在过去的几十年里，人们广泛研究了 C-X-C 受体 (CXCR) 7 及其密切合作伙伴 CXCR4 在不同生理和病理生理过程中的作用。在被其共同配体 C-X-C 配体 (CXCL) 12 激活后，这两种趋化因子受体可以诱导各种细胞信号通路，并/或从细胞外环境中清除 CXCL12。这有助于器官发育和维持体内平衡。在癌症、中枢神经系统和心脏疾病以及自身免疫性疾病等疾病中已经检测到 CXCR4/CXCR7-CXCL12 轴的改变。这些改变包括表达模式、分布或下游效应的变化。在临床前模型中，通过使用各种调节剂可以调节疾病的进展，这表明该轴是一个很有前途的治疗靶点。因此，研究 CXCR4/CXCR7/CXCL12 调节剂在临床开发中的作用具有重要意义，目前已经有几种 CXCR4 和 CXCL12 调节剂，如plerixafor、ulocuplumab、balixafortide 和 olaptesed pegol，已经进入这一阶段。本文综述了最重要的疾病，其结局可以通过 CXCR4/CXCR7-CXCL12 轴的正或负调节来改善，并总结了该轴调节剂的临床前和临床数据。与 CXCR4 和 CXCL12 调节剂不同，迄今为止，CXCR7 调节剂尚未得到广泛研究。因此，需要更多的（临床前）研究。
