2. Academic Validation
  3. 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

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.
Salvatore Di Maro 1,  Anna Maria Trotta 2,  Diego Brancaccio 3 4,  Francesco Saverio Di Leva 3,  Valeria La Pietra 3,  Caterina Ieranò 2,  Maria Napolitano 2,  Luigi Portella 2,  Crescenzo D'Alterio 2,  Rosa Anna Siciliano 5,  Deborah Sementa 3,  Stefano Tomassi 3,  Alfonso Carotenuto 3,  Ettore Novellino 3,  Stefania Scala 2,  Luciana Marinelli 3
Affiliations

Affiliations

  • 1 DiSTABiF, Second University of Naples , Via Vivaldi 43, 81100 Caserta, Italy.
  • 2 Genomica Funzionale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "Giovanni Pascale", IRCCS-ITALY , Via M. Semmola, 80131 Naples, Italy.
  • 3 Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II" , via D. Montesano 49, 80131 Naples, Italy.
  • 4 Laboratory of Food Chemistry, Dipartimento di Agraria (QuaSic.A.Tec.), Università Mediterranea di Reggio Calabria , Reggio Calabria, loc. Feo di Vito, 89122 Reggio Calabria, Italy.
  • 5 Istituto di Scienze dell'Alimentazione, CNR , Via Roma 64, 83100 Avellino, Italy.
PMID: 27571038 DOI: 10.1021/acs.jmedchem.6b00695
Abstract

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.

Figures
Products