Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 186, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.111891
Keywords
ALT; Telomere; Multimeric G-quadruplex; Dimeric ligand; Selective
Categories
Funding
- National Natural Science Foundation of China [81803348]
- Natural Science Foundation of Guangdong Province [2018A030310580]
- Shenzhen Science and Technology Innovation Commission [JCYJ20170818141916158]
- Medical Science and Technology Foundation of Guangdong Province [A2019001]
- Natural Science Research Project of Shenzhen University
- SZU Medical Young Scientists Program
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In 10-15% of cancers, telomere maintenance is provided by a telomerase-independent mechanism known as alternative lengthening of telomere (ALT), making telomerase inhibitors ineffective on these cancers. Ligands that stabilize telomeric G-quadruplex (G4) are considered to be able to inhibit either the ALT process or disrupt the T-loop structure, which would be promising therapeutic agents for ALT cancers. Notably, the 3'-terminal overhang of telomeric DNA might fold into multimeric G4 containing consecutive G4 subunits, which offers an attractive target for selective ligands considering large numbers of G4s widespread in the genome. In this study, a dimeric aryl-substituted imidazole (DIZ-3) was developed as a selective multimeric G4 ligand based on a G4-ligand-dimerizing strategy. Biophysical experiments revealed that DIZ-3 intercalated into the G4-G4 interface, stabilizing the higher-order structure. Furthermore, this ligand was demonstrated to induce cell cycle arrest and apoptosis, and thus inhibited cell proliferation in an ALT cancer cell line. Cancer cells were more sensitive to DIZ-3, relative to normal cells. Notably, DIZ-3 had little effect on the transcription of several G4-dependent oncogenes. This study provides a nice example for discovering dimeric agents to potentially treat ALT cancers via targeting telomeric multimeric G4. (C) 2019 Elsevier Masson SAS. All rights reserved.
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