Structure-Activity Relationships and Biological Characterization of a Novel, Potent, and Serum Stable C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonist

Salvatore Di Maro, Francesco Saverio Di Leva, Anna Maria Trotta, Diego Brancaccio, Luigi Portella, Michela Aurilio, Stefano Tomassi, Anna Messere, Deborah Sementa, Secondo Lastoria, Alfonso Carotenuto, Ettore Novellino, Stefania Scala, Luciana Marinelli

Research output: Contribution to journalArticle

Abstract

In our ongoing pursuit of CXCR4 antagonists as potential anticancer agents, we recently developed a potent, selective, and plasma stable peptide, Ac-Arg-Ala-[d-Cys-Arg-Phe-Phe-Cys]-COOH (3). Nevertheless, this compound was still not potent enough (IC50 ≈ 53 nM) to enter preclinical studies. Thus, a lead-optimization campaign was here undertaken to further improve the binding affinity of 3 while preserving its selectivity and proteolytic stability. Specifically, extensive structure-activity relationships (SARs) investigations were carried out on both its aromatic and disulfide forming amino acids. One among the synthesized analogue, Ac-Arg-Ala-[d-Cys-Arg-Phe-His-Pen]-COOH (19), displayed subnanomolar affinity toward CXCR4, with a marked selectivity over CXCR3 and CXCR7. NMR and molecular modeling studies disclosed the molecular bases for the binding of 19 to CXCR4 and for its improved potency compared to the lead 3. Finally, biological assays on specific cancer cell lines showed that 19 can impair CXCL12-mediated cell migration and CXCR4 internalization more efficiently than the clinically approved CXCR4 antagonist plerixafor.

Original languageEnglish
Pages (from-to)9641-9652
Number of pages12
JournalJournal of Medicinal Chemistry
Volume60
Issue number23
DOIs
Publication statusPublished - Dec 14 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Di Maro, S., Di Leva, F. S., Trotta, A. M., Brancaccio, D., Portella, L., Aurilio, M., Tomassi, S., Messere, A., Sementa, D., Lastoria, S., Carotenuto, A., Novellino, E., Scala, S., & Marinelli, L. (2017). Structure-Activity Relationships and Biological Characterization of a Novel, Potent, and Serum Stable C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonist. Journal of Medicinal Chemistry, 60(23), 9641-9652. https://doi.org/10.1021/acs.jmedchem.7b01062