Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors
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Embargo End Date
ICR Authors
Authors
Read, M
Harrison, RJ
Romagnoli, B
Tanious, FA
Gowan, SH
Reszka, AP
Wilson, WD
Kelland, LR
Neidle, S
Harrison, RJ
Romagnoli, B
Tanious, FA
Gowan, SH
Reszka, AP
Wilson, WD
Kelland, LR
Neidle, S
Document Type
Journal Article
Date
2001-04-24
Date Accepted
Abstract
<jats:p>
The telomerase enzyme is a potential therapeutic target in
many human cancers. A series of potent inhibitors has been designed by
computer modeling, which exploit the unique structural features of
quadruplex DNA. These 3,6,9-trisubstituted acridine inhibitors are
predicted to interact selectively with the human DNA quadruplex
structure, as a means of specifically inhibiting the action of human
telomerase in extending the length of single-stranded telomeric DNA.
The anilino substituent at the 9-position of the acridine chromophore
is predicted to lie in a third groove of the quadruplex. Calculated
relative binding energies predict enhanced selectivity compared with
earlier 3,6-disubstituted compounds, as a result of this substituent.
The ranking order of energies is in accord with equilibrium binding
constants for quadruplex measured by surface plasmon resonance
techniques, which also show reduced duplex binding compared with the
disubstituted compounds. The 3,6,9-trisubstututed acridines have potent
<jats:italic>in vitro</jats:italic>
inhibitory activity against human telomerase,
with EC
<jats:sub>50</jats:sub>
values of up to 60 nM.
</jats:p>
Citation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 pp. 4844 - 4849
Source Title
Publisher
Proceedings of the National Academy of Sciences
ISSN
0027-8424