title: A G-quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity.
abstract: The telomerase complex is responsible for telomere maintenance and represents a promising cancer therapeutic target. We describe herein the antitelomerase and antitumor properties 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 acridine 9-[4-(N,N-dimethylamino)phenylamino]-3,6-bis(3-pyrrolodinopropionamido) 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 described previously, BRACO19 did not cause nonspecific acute cytotoxicity at similar concentrations to those required to completely inhibit telomerase activity. There exists a 90-fold differential (mean 50% inhibitory concentration for acute cell kill across seven human tumor cell lines of 10.6 +/- 0.7 microM). The exposure of 21NT human breast cancer cells, which possess relatively short telomeres, to nonacute cytotoxic concentrations of BRACO19 (2 microM) resulted in a marked reduction in cell growth after only 15 days. This was concomitant with a reduction in intracellular telomerase activity and onset of senescence as indicated by an increase in the number of beta-galactosidase positive-staining cells. Intraperitoneal administration of nontoxic doses of BRACO19 (2 mg/kg) to mice bearing advanced stage A431 human vulval carcinoma subcutaneous xenografts and previously treated with paclitaxel induced a significant increase in antitumor effect compared with that observed with paclitaxel alone. BRACO19 thus represents the first of a "second generation" of G-quadruplex-mediated telomerase/telomere-interactive compounds. It possesses nanomolar potency against telomerase but low nonspecific cytotoxicity, growth inhibitory effects, and induction of senescence in a human breast cancer cell line and, moreover, significant antitumor activity in vivo when administered post paclitaxel to mice bearing a human tumor xenograft carcinoma.
authors.affiliation: Cancer Research Campaign (CRC) Center for Cancer Therapeutics, Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Gowan
authors.forename: John R
authors.initials: JR
authors.lastname: Harrison
authors.forename: Lisa
authors.initials: L
authors.lastname: Patterson
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Martin A
authors.initials: MA
authors.lastname: Read
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Lloyd R
authors.initials: LR
authors.lastname: Kelland
mesh_terms: D000166:Acridines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000187:drug effects*; D004195:Disease Models, Animal; D054856:G-Quadruplexes; D006801:Humans; D016867:Immunocompromised Host; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D004247:DNA; D019098:Telomerase; C454064:BRACO-19