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 M 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 furtherG-quadruplex units are added.