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Publication Abstract from PubMed

We previously reported the discovery of a CXCL12-mimetic cyclic peptide (2) as 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 leukaemia (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 leukaemia and colon cancer.

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.,Di Maro S, Trotta AM, Brancaccio D, Di Leva FS, La Pietra V, Ierano C, Napolitano M, Portella L, D'Alterio C, Siciliano RA, Sementa D, Tomassi S, Carotenuto A, Novellino E, Scala S, Marinelli L J Med Chem. 2016 Aug 29. PMID:27571038^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.