Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond

Abstract

The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4 cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., 16) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug 1 (AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound 16 into the X-ray crystal structure of CXCR4 receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 receptor-ligand interactions for further structural modifications.

Recent Advances in CXCL12/CXCR4 Antagonists and Nano-Based Drug Delivery Systems for Cancer Therapy

“…The chemical structures of some representative small-molecule compounds are given in Figure 2 a. We also show the X-ray structure of CXCR4 interacting with one of its antagonists in Figure 2 b [ 75 ].…”

Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration

“…Meanwhile, AMD3100 has served as the model for the exploration of novel stem cell mobilizers that target the CXCR4 receptor, 93 and that could be considered as potential drug candidates, i.e. KRH-1636 94 (Figure 3), and CX0714 95 (Figure 3), which may be useful as stem cell-mobilizing agents for the same indications that have so far been considered for AMD3100.…”

Discovery of Potential Neuroprotective Agents against Paclitaxel-Induced Peripheral Neuropathy

“…As a result, a class of structurally closely related pyrimidine compounds, originally designed to target G protein-coupled CXC chemokine receptor 4 (CXCR4) for disease indications such as peripheral stem-cell transplantation, hemorrhagic stroke, hepatocellular carcinoma, and so forth − but failed to show any significant activities towards CXCR4 receptors, were unexpectedly detected (Figure ). All these 19 compounds were then subjected to the neurite outgrowth assay of dorsal root ganglion (DRG) neurons paired with an image-based HCS to analyze whether they had neuroprotective potential.…”