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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. 61(3)
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Male
Cell type
Benzylamines
Receptors, CXCR4
Protein Conformation
Inflammation
Cyclams
CXCR4
03 medical and health sciences
Inhibitory Concentration 50
Mice
0302 clinical medicine
Heterocyclic Compounds
Drug Discovery
medicine
Animals
Humans
Receptor
Peripheral Blood Stem Cell Transplantation
Chemistry
Stem Cells
HEK 293 cells
Molecular Docking Simulation
030104 developmental biology
medicine.anatomical_structure
HEK293 Cells
Docking (molecular)
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Bone marrow
Stem cell
medicine.symptom
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 61
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....673e4a8498bb2f6a8a1ac4e555d7c1e3