Vol. 63, Issue 5, 1117-1124, May 2003

Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives

Joo Hee Kim, Jun Hyun Kim, Gun Eui Lee, Jong Eun Lee, and In Kwon Chung

DNA Link, Milk Building (J.H.K., J.H.K., J.E.L.), and Department of Biology, Molecular Aging Research Center, and Protein Network Research Center (G.E.L., I.K.C.), Yonsei University, Seoul, Korea

Telomerase activity is expressed in most types of cancer cells but not in normal somatic cells, suggesting that telomerase may be an important target for cancer chemotherapy. Inhibition of telomerase results in telomere erosion, leading to the subsequent growth arrest of cancer cells followed by senescence or cell death. In this study, we screened a chemical library for the inhibition of human telomerase, identifying three inhibitors. All compounds contained a common nitrostyrene moiety conjugated to different side chains. One of these compounds, 3-(3,5-dichlorophenoxy)-nitrostyrene (DPNS), showed the most potent inhibitory effect, with 50% inhibition at ~0.4 µM and did not inhibit DNA and RNA polymerases, including retroviral reverse transcriptase. A series of enzyme kinetic experiments suggests that DPNS is a mixed-type noncompetitive inhibitor, with an inhibitor-binding site distinct from the binding sites for the telomeric substrate primer and the deoxynucleoside-5'-triphosphates. Extensive propagation of cancer cell line in the presence of DPNS resulted in progressive telomere erosion followed by the induction of senescence phenotype. The results presented here demonstrate that DPNS is a highly selective, small-molecule telomerase inhibitor in vitro and could be useful as a lead molecule for the further development of inhibitors with an improved potential for efficacy in vivo.