PT  - JOURNAL ARTICLE
AU  - Joo Hee Kim
AU  - Jun Hyun Kim
AU  - Gun Eui Lee
AU  - Jong Eun Lee
AU  - In Kwon Chung
TI  - Potent Inhibition of Human Telomerase by Nitrostyrene Derivatives
AID  - 10.1124/mol.63.5.1117
DP  - 2003 May 01
TA  - Molecular Pharmacology
PG  - 1117--1124
VI  - 63
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/63/5/1117.short
4100  - http://molpharm.aspetjournals.org/content/63/5/1117.full
SO  - Mol Pharmacol2003 May 01; 63
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics