Discovery of Novel Stem Cell Mobilizers That Target the CXCR4 Receptor

Wu, Chien-Huang; Chang, C. P.; Song, Jen‐Shin; Jan, Jiing-Jyh; Chou, Ming‐Chen; Wu, Szu-Huei; Yeh, Kai-Chia; Wong, Ying‐Chieh; Hsieh, Chieh-Jui; Chen, Chiung‐Tong; Kao, Tzu‐Ting; Wu, Su-Ying; Yeh, Ching-Fang; Tseng, Chen‐Tso; Chao, Yu‐Sheng; Shia, Kak‐Shan

doi:10.1002/cmdc.201100525

Cited by 19 publications

(27 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A high-throughput screening campaign to search for new CXCR4 antagonists revealed quinoline and quinazoline derivatives as candidates, where the hit ligand shows a 5-fold higher affinity in inhibition of 125 I-CXCL12 binding to CXCR4 (IC 50 5 4.7 nM) compared with AMD3100 (IC 50 5 213 nM) (Wu et al, 2012). Another potent quinazoline-based selective CXCR4 antagonist (compound 1, Fig.…”

Section: Downloaded Frommentioning

confidence: 99%

Modulators of CXCR4 and CXCR7/ACKR3 Function

et al. 2019

View full text Add to dashboard Cite

The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the smallmolecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio-and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo. SIGNIFICANCE STATEMENTTo investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins, and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors.

show abstract

Section: Downloaded Frommentioning

confidence: 99%

Modulators of CXCR4 and CXCR7/ACKR3 Function

et al. 2019

View full text Add to dashboard Cite

show abstract

“…). For the functional studies, one of the most potent compounds, 95 exhibited comparable stem cell mobilization as AMD3100 from the bone marrow …”

Section: Therapeutic Potential For Intervention With Cxcl12/cxcr4 Axismentioning

confidence: 99%

“…Compared to compound 95 (IC 50 = 34.2 ± 3.1 nM, a significant reduction in CXCR4 binding by compound 126 (IC 50 = 156.0 ± 19.8 nM) was observed when the bisbenzyl moiety was replaced with a triazole ring . To probe the optimal spatial orientation of the two essential secondary nitrogen elements in the lower chain, compounds 127 and 128 (IC 50 = 30–39 nM), both of which contain a linker with five methylene units, exhibited a significant improvement in CXCR4 binding affinities compared to those containing linkers with four methylene units (IC 50 = 156–250 nM).…”

Section: Therapeutic Potential For Intervention With Cxcl12/cxcr4 Axismentioning

confidence: 99%

“…For the functional studies, one of the most potent compounds, 95 exhibited comparable stem cell mobilization as AMD3100 from the bone marrow. 271 In a separate study, the potential of these quinazoline-based CXCR4 antagonists in the blockade of HIV-1 entry was evaluated by luciferase activity assays using TZM-bl cells. 99 Compounds 92-96 with terminal ring-size expansion from three-to seven-membered ring showed increased binding affinities toward the CXCR4 receptor and relatively good correlation with their anti-HIV-1 activities.…”

Section: Quinazoline-based Antagonistsmentioning

confidence: 99%

“…(IC 50 = 156.0 ± 19.8 nM) was observed when the bisbenzyl moiety was replaced with a triazole ring. 271 To probe the optimal spatial orientation of the two essential secondary nitrogen elements in the lower chain, in vivo. 178 Further study of compound 129 in the treatment of renal ischemia-reperfusion injury showed that it significantly lowered levels of blood urea nitrogen and serum creatinine, providing evidence that circulating adult stem cells could exert beneficial effects on damaged tissues in diseases that currently are not treated by standard approaches.…”

Section: Quinazoline-triazole Based Antagonistsmentioning

confidence: 99%

See 2 more Smart Citations

Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology

Tsou

Huang²,

Song

et al. 2017

Medicinal Research Reviews

Self Cite

View full text Add to dashboard Cite

CXCR4 antagonists (e.g., Plerixafor ) have been successfully validated as stem cell mobilizers for peripheral blood stem cell transplantation. Applications of the CXCR4 antagonists have heralded the era of cell-based therapy and opened a potential therapeutic horizon for many unmet medical needs such as kidney injury, ischemic stroke, cancer, and myocardial infarction. In this review, we first introduce the central role of CXCR4 in diverse cellular signaling pathways and discuss its involvement in several disease progressions. We then highlight the molecular design and optimization strategies for targeting CXCR4 from a large number of case studies, concluding that polyamines are the preferred CXCR4-binding ligands compared to other structural options, presumably by mimicking the highly positively charged natural ligand CXCL12. These results could be further justified with computer-aided docking into the CXCR4 crystal structure wherein both major and minor subpockets of the binding cavity are considered functionally important. Finally, from the clinical point of view, CXCR4 antagonists could mobilize hematopoietic stem/progenitor cells with long-term repopulating capacity to the peripheral blood, promising to replace surgically obtained bone marrow cells as a preferred source for stem cell transplantation.

show abstract

Inhibition of the CXCL12/CXCR4 axis prevents periurethral collagen accumulation and lower urinary tract dysfunction in vivo

et al. 2019

View full text Add to dashboard Cite

Background Several studies show that prostatic fibrosis is associated with male lower urinary tract dysfunction (LUTD). Development of fibrosis is typically attributed to signaling through the transforming growth factor β (TGF‐β) pathway, but our laboratory has demonstrated that in vitro treatment of human prostatic fibroblasts with the C‐X‐C motif chemokine ligand 12 (CXCL12) chemokine stimulates myofibroblast phenoconversion and that CXCL12 has the capacity to activate profibrotic pathways in these cells in a TGF‐β‐independent manner. We have previously reported that feeding mice high‐fat diet (HFD) results in obesity, type II diabetes, increased prostatic fibrosis, and urinary voiding dysfunction. The purpose of this study was to test the hypothesis that in vivo blockade of the CXCL12/CXCR4 axis would inhibit the development of fibrosis‐mediated LUTD in HFD‐fed mice. Methods Two‐month‐old male senescence‐accelerated mouse prone‐6 mice were fed either a HFD or low‐fat diet (LFD) for 8 months. Half of each dietary group were given constant access to normal water or water that contained the C‐X‐C chemokine receptor type 4 (CXCR4; CXCL12 receptor) antagonist CXCR4AIII. At the conclusion of the study, mice were weighed, subjected to oral glucose tolerance testing and cystometry, and lower urinary tract tissues collected and assessed for collagen content. Results HFD‐fed mice became significantly obese, insulin resistant, and hyperglycemic, consistent with acquisition of metabolic syndrome, compared with LFD‐fed mice. Anesthetized cystometry demonstrated that HFD‐fed mice experienced significantly longer intercontractile intervals and greater functional bladder capacity than LFD‐fed mice. Immunohistochemistry demonstrated high levels of CXCR4 and CXCR7 staining in mouse prostate epithelial and stromal cells. Picrosirius red staining indicated significantly greater periurethral collagen deposition in the prostates of HFD than LFD‐fed mice. Treatment with the CXCR4 antagonist CXCR4AIII did not affect acquisition of metabolic syndrome but did reduce both urinary voiding dysfunction and periurethral prostate collagen accumulation. Conclusions This is the first study to report that obesity‐induced lower urinary tract fibrosis and voiding dysfunction can be repressed by antagonizing the activity of the CXCR4 chemokine receptor in vivo. These data suggest that targeting the CXCL12/CXCR4 signaling pathway may be a clinical option for the prevention or treatment of human male LUTD.

show abstract

Discovery of Novel Stem Cell Mobilizers That Target the CXCR4 Receptor

Cited by 19 publications

References 27 publications

Modulators of CXCR4 and CXCR7/ACKR3 Function

Modulators of CXCR4 and CXCR7/ACKR3 Function

Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology

Inhibition of the CXCL12/CXCR4 axis prevents periurethral collagen accumulation and lower urinary tract dysfunction in vivo

Contact Info

Product

Resources

About