BMPQ-1 binds selectively to (3+1) hybrid topologies in human telomeric G-quadruplex multimers.
Animals
Apoptosis
/ drug effects
Cell Cycle
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Circular Dichroism
DNA Damage
Fluorescence Resonance Energy Transfer
G-Quadruplexes
Humans
Inhibitory Concentration 50
Ligands
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasms
/ drug therapy
Nucleic Acid Conformation
Quinazolines
/ chemistry
Telomere
/ chemistry
Xenograft Model Antitumor Assays
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
18 11 2020
18 11 2020
Historique:
accepted:
14
10
2020
revised:
23
09
2020
received:
10
05
2020
pubmed:
21
10
2020
medline:
29
12
2020
entrez:
20
10
2020
Statut:
ppublish
Résumé
A single G-quadruplex forming sequence from the human telomere can adopt six distinct topologies that are inter-convertible under physiological conditions. This presents challenges to design ligands that show selectivity and specificity towards a particular conformation. Additional complexity is introduced in differentiating multimeric G-quadruplexes over monomeric species, which would be able to form in the single-stranded 3' ends of telomeres. A few ligands have been reported that bind to dimeric quadruplexes, but their preclinical pharmacological evaluation is limited. Using multidisciplinary approaches, we identified a novel quinoline core ligand, BMPQ-1, which bound to human telomeric G-quadruplex multimers over monomeric G-quadruplexes with high selectivity, and induced the formation of G-quadruplex DNA along with the related DNA damage response at the telomere. BMPQ-1 reduced tumor cell proliferation with an IC50 of ∼1.0 μM and decreased tumor growth rate in mouse by half. Biophysical analysis using smFRET identified a mixture of multiple conformations coexisting for dimeric G-quadruplexes in solution. Here, we showed that the titration of BMPQ-1 shifted the conformational ensemble of multimeric G-quadruplexes towards (3+1) hybrid-2 topology, which became more pronounced as further G-quadruplex units are added.
Identifiants
pubmed: 33080032
pii: 5932844
doi: 10.1093/nar/gkaa870
pmc: PMC7672424
doi:
Substances chimiques
Ligands
0
Quinazolines
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11259-11269Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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