Journal
CHEMMEDCHEM
Volume 15, Issue 13, Pages 1150-1162Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000268
Keywords
Chemokines; CXCL12; CXCR4; G protein-coupled receptors
Categories
Funding
- National Natural Science Foundation of China [81973161, 81773561, 21502133]
- Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)
- Jiangsu Key Laboratory of Neuropsychiatric Diseases [BM2013003]
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Chemokine receptor CXCR4 and its natural ligand CXCL12 (also known as stromal cell-derived factor-1, or SDF-1) regulate a broad range of physiological functions. Dysregulation of the CXCL12/CXCR4 axis is involved in numerous pathological conditions such as HIV infection, inflammation and cancer. Herein, we report the design, synthesis, and characterization of novel CXCR4 antagonists based on cyclic amine scaffolds. Compound 24 was identified as a potent CXCR4 receptor antagonist (competitive inhibition of 12G5 binding, IC50=24 nM; functional inhibition of CXCL12-induced cytosolic calcium increase, IC50=0.1 nM). In addition, compound 24 potently inhibited cell migration in CXCR4/CXCL12-mediated chemotaxis in a matrigel invasion assay. The absolute configuration of compound 24 was elucidated by X-ray crystallography.
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