Potent inhibition of human telomerase by nitrostyrene derivatives

Joo Hee Kim, Jun Hyun Kim, Gun Eui Lee, Jongeun Lee, In Kwon Chung

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1117-1124
Number of pages8
JournalMolecular Pharmacology
Volume63
Issue number5
DOIs
Publication statusPublished - 2003 May 1

Fingerprint

Telomerase
Telomere
Neoplasms
Binding Sites
Small Molecule Libraries
Cell Aging
RNA-Directed DNA Polymerase
DNA-Directed DNA Polymerase
DNA-Directed RNA Polymerases
Cell Death
Phenotype
Drug Therapy
Cell Line
Enzymes
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Kim, Joo Hee ; Kim, Jun Hyun ; Lee, Gun Eui ; Lee, Jongeun ; Chung, In Kwon. / Potent inhibition of human telomerase by nitrostyrene derivatives. In: Molecular Pharmacology. 2003 ; Vol. 63, No. 5. pp. 1117-1124.
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Potent inhibition of human telomerase by nitrostyrene derivatives. / Kim, Joo Hee; Kim, Jun Hyun; Lee, Gun Eui; Lee, Jongeun; Chung, In Kwon.

In: Molecular Pharmacology, Vol. 63, No. 5, 01.05.2003, p. 1117-1124.

Research output: Contribution to journalArticle

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