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Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond
- Source :
- Journal of Medicinal Chemistry; 20240101, Issue: Preprints
- Publication Year :
- 2024
-
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 16into 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.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Issue :
- Preprints
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs44407784
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b01322