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Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)
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Online ISSN: 1860-7187
December 23, 2011
VIP: Discovery of Novel Stem Cell Mobilizers That Target the CXCR4 Receptor
Chien-Huang Wu, Chun-Ping Chang, Jen-Shin Song, Jiing-Jyh Jan, Ming-Chen Chou, Szu-Huei Wu, Kai-Chia Yeh, Ying-Chieh Wong, Chieh-Jui Hsieh, Chiung-Tong Chen, Tzu-Ting Kao, Su-Ying Wu, Ching-Fang Yeh, Chen-Tso Tseng, Yu-Sheng Chao, and Kak-Shan Shia*
The CXCR4 chemokine receptor along with its endogenous ligand CXCL12 plays a pivotal role in homing and mobilization of many stem cell types, such as hematopoietic stem cells (HSC), endothelial progenitor cells (EPC), and mesenchymal stem cells (MSC). By blocking the CXCL12–CXCR4 interaction, CXCR4 antagonists could see therapeutic use as anti-HIV, anti-metastasis, anti-cancer, and anti-inflammation agents, and could also be used in tissue repair.
A collaborative research team led by Kak-Shan Shia at the National Health Research Institutes (Taiwan, ROC) has disclosed a new series of CXCR4 antagonists based on a high-throughput screening hit by a scaffold-hopping synthetic strategy. Biological assays and animal efficacy studies show that these compounds are as potent as the current commercial drug AMD3100 (plerixafor, MozobilTM) in mobilizing HSC, particularly CD34+ and CD133+ cell types, to the peripheral circulatory system from bone marrow.
As supported by many historical cases, the results reported by Shia and colleagues also strongly suggest that the incorporation of adequate N-containing fragments with an active core skeleton is essential for the design of potent and specific CXCR4 antagonists; this is presumably due to mimicry of the Lys/Arg-rich nature of the CXCL12 ligand itself. Because CXCR4 antagonists are able to mobilize adult stem cells from bone marrow without the need for surgery, they hold significant potential in cell therapy and regenerative medicine such as ischemic stroke recovery and heart tissue repair.
Received November 14, 2011; published online December 20, 2011, DOI: 10.1002/cmdc.201100525.