Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors

The telomerase enzyme is a potential therapeutic target in many human cance rs. A series of potent inhibitors has been designed by computer modeling, w hich exploit the unique structural features of quadruplex DNA, These 3,6,9- trisubstituted acridine inhibitors are predicted to interact selectively wi th the human DNA quadruplex structure, as a means of specifically inhibitin g 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. Calcul ated relative binding energies predict enhanced selectivity compared with e arlier 3,6-disubstituted compounds, as a result of this substituent, The ra nking order of energies is in accord with equilibrium binding constants for quadruplex measured by surface plasmon resonance techniques, which also sh ow reduced duplex binding compared with the disubstituted compounds. The 3, 6,9-trisubstututed acridines have potent in vitro inhibitory activity again st human telomerase. with EC50 values of up to 60 nM.