Exploring the N-Terminal Region of C-X-C Motif Chemokine 12 (CXCL12): Identification of Plasma-Stable Cyclic Peptides As Novel, Potent C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonists

J Med Chem. 2016 Sep 22;59(18):8369-80. doi: 10.1021/acs.jmedchem.6b00695. Epub 2016 Sep 9.


We previously reported the discovery of a CXCL12-mimetic cyclic peptide (2) as a selective CXCR4 antagonist showing promising in vitro and in vivo anticancer activity. However, further development of this peptide was hampered by its degradation in biological fluids as well as by its low micromolar affinity for the receptor. Herein, extensive chemical modifications led to the development of a new analogue (10) with enhanced potency, specificity, and plasma stability. A combined approach of Ala-amino acid scan, NMR, and molecular modeling unraveled the reasons behind the improved binding properties of 10 vs 2. Biological investigations on leukemia (CEM) and colon (HT29 and HCT116) cancer cell lines showed that 10 is able to impair CXCL12-mediated cell migration, ERK-phosphorylation, and CXCR4 internalization. These outcomes might pave the way for the future preclinical development of 10 in CXCR4 overexpressing leukemia and colon cancer.

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chemokine CXCL12 / chemistry*
  • Chemokine CXCL12 / pharmacology*
  • Colonic Neoplasms / drug therapy
  • Humans
  • Leukemia / drug therapy
  • Models, Molecular
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology*
  • Phosphorylation / drug effects
  • Receptors, CXCR4 / antagonists & inhibitors*


  • Antineoplastic Agents
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Peptides, Cyclic
  • Receptors, CXCR4