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.
| Original language | English |
|---|---|
| Pages (from-to) | 8369-8380 |
| Number of pages | 12 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 59 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - Sep 22 2016 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
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, Salvatore; Trotta, Anna Maria; Brancaccio, Diego; Di Leva, Francesco Saverio; La Pietra, Valeria; Ieranò, Caterina; Napolitano, Maria; Portella, Luigi; D'Alterio, Crescenzo; Siciliano, Rosa Anna; Sementa, Deborah; Tomassi, Stefano; Carotenuto, Alfonso; Novellino, Ettore; Scala, Stefania; Marinelli, Luciana.
In: Journal of Medicinal Chemistry, Vol. 59, No. 18, 22.09.2016, p. 8369-8380.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Exploring the N-Terminal Region of C-X-C Motif Chemokine 12 (CXCL12)
T2 - Identification of Plasma-Stable Cyclic Peptides As Novel, Potent C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonists
AU - Di Maro, Salvatore
AU - Trotta, Anna Maria
AU - Brancaccio, Diego
AU - Di Leva, Francesco Saverio
AU - La Pietra, Valeria
AU - Ieranò, Caterina
AU - Napolitano, Maria
AU - Portella, Luigi
AU - D'Alterio, Crescenzo
AU - Siciliano, Rosa Anna
AU - Sementa, Deborah
AU - Tomassi, Stefano
AU - Carotenuto, Alfonso
AU - Novellino, Ettore
AU - Scala, Stefania
AU - Marinelli, Luciana
PY - 2016/9/22
Y1 - 2016/9/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84988733628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84988733628&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b00695
DO - 10.1021/acs.jmedchem.6b00695
M3 - Article
AN - SCOPUS:84988733628
VL - 59
SP - 8369
EP - 8380
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 18
ER -