Stem Cell Mobilizers Targeting Chemokine Receptor CXCR4: Renoprotective Application in Acute Kidney Injury

Abstract

We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4(+) cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches.

Structural Analysis of Chemokine Receptor–Ligand Interactions

“…The representative CXCR4 ligands include compounds 31 , 80 32 , 154 33 – 34 , 155,156 35 , 157,187 36 , 158 and 37 ; 36 CCR5 ligands include compounds, 38 , 172 39 , 188 40 , 159 41 , 189 42 , 161 43 , 162 and 44 . 163 US28 ligands include compounds 45 , 180 46 , 47 , 181 48 , 182 49 , 181 50 , 184 51 , 185 and 52 .…”

“…D171 4.60 N, D262 6.58 N, and E288 7.39 Q mutations resulted in a significant decrease of binding of 1 – 13 68−72 and 15 , 21 supporting a binding mode in which these negatively ionizable residues are involved in ionic interactions with the positively charged basic nitrogen atoms of ligands 1 – 13 and 15 (Figure 11). SAR studies have indeed indicated that the cationic basic moieties of 15 , 151,152 13 , 153 31 , 78 32 (WZ811), 154 33 , and 34 (155,156) are essential for CXCR4 binding (Figure 11). In addition, Y45 1.39 A, W90 2.60 A, and Y116 3.32 A mutations affected the affinity of 1 , 2 , and 13 , 69 while Q200 5.39 A and H281 7.32 A mutation affected potency of 2 , 3 , and 4 .…”

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

“…It was shown in rat models that treatment with CXCR4 antagonists significantly lowered levels of blood urea nitrogen and serum creatinine 24 hr after bilateral renal ischemia-reperfusion injury. [176][177][178] These data provided evidence that CXCR4 antagonism might be useful to increase circulating levels of adult stem cells or to reduce leukocytes infiltration into kidney, thereby exerting beneficial effects on prevention of ischemic kidney damage.…”

“…In a separate study on the ability of the quinazoline analogs to mobilize stem cells, a novel series of triazole ring containing polyamines were synthesized (Fig. ) …”

“…Compound 130 , which contains a seven methylene unit linker, is less potent with an IC 50 value of 84.5 nM . Considering its potent binding ability (IC 50 = 12.6 ± 0.9 nM), compound 129 was shown to mobilize HSCs and endothelial progenitor cells more efficiently than AMD3100 when administered at the same dose in vivo . 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 …”