A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity

The telomerase complex is responsible for telomere mainte-nance and represents a promising cancer therapeutic target. We describe herein the antitelomerase and antitumor proper-ties of a small-molecule compound designed by computer modeling to interact with and stabilize human G-quadruplex DNA, a structure that may form with telomeric DNA, thereby inhibiting access to telomerase. The 3,6,9-trisubstituted acri-dine 9-[4-(N,N-dimethylamino)phenylamino]-3,6-bis(3-pyr-rolodinopropionamido) acridine (BRACO19) represents one of the most potent cell-free inhibitors of human telomerase yet described (50 % inhibitory concentration of 115 18 nM). Moreover, in contrast to G-quadruplex interactive agents de-scribed previously, BRACO19 did not cause nonspecific acute cytotoxicity at similar concentrations to those required to com