Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors.
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 in vitro inhibitory activity against human telomerase, with EC(50) values of up to 60 nM.
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Cancer Research Campaign Biomolecular Structure Unit, Chester Beatty Laboratories, The Institute of Cancer Research, London SW3 6JB, United Kingdom.
Harrison
R J
RJ
Romagnoli
B
B
Tanious
F A
FA
Gowan
S H
SH
Reszka
A P
AP
Wilson
W D
WD
Kelland
L R
LR
Neidle
S
S
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003198:Computer Simulation; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D054856:G-Quadruplexes; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D010051:Ovarian Neoplasms / Q000473:pathology; D012996:Solutions; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013816:Thermodynamics; D014407:Tumor Cells, Cultured
D000166:Acridines; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D012996:Solutions; D004247:DNA; D019098:Telomerase