5OJT

Structure-Activity Relationships and Biological Characterization of a Novel, Potent and Serum Stable C-X-C chemokine receptor type 4 (CXCR4) Antagonist

5OJT の概要

• エントリーDOI: 10.2210/pdb5ojt/pdb
• NMR情報: BMRB: 34165
• 分子名称: ACE-ARG-ALA-(D)CYS-ARG-BNA-HIS-PEN (1 entity in total)
• 機能のキーワード: cxcr4, peptide binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 999.24

構造登録者

Brancaccio, D.,Carotenuto, A. (登録日: 2017-07-24, 公開日: 2017-11-22, 最終更新日: 2023-11-15)

主引用文献

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.
Structure-Activity Relationships and Biological Characterization of a Novel, Potent, and Serum Stable C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonist.
J. Med. Chem., 60:9641-9652, 2017

PubMed 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 (IC ≈ 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.

PubMed: 29125295
DOI: 10.1021/acs.jmedchem.7b01062

実験手法

SOLUTION NMR