FJ5002: a potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE analysis.
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| Abstract |
To facilitate the search for candidate telomerase inhibitors, we exploited the database of the disease-oriented screening program (DOS) available in our facility by using COMPARE analysis. In primary and arbitrary screening, we were able to identify the alkaloid berberine as a moderate inhibitor with 50% inhibition at approximately 35 microM. Using this alkaloid as a seed compound in COMPARE resulted in the identification of other berberine-like compounds and mitochondria-accumulating agents as highly related to berberine. Among these compounds, MKT077, a rhodacyanine derivative currently under Phase I clinical trials, showed a potent inhibitory effect with 50% inhibition at approximately 5 microM. With MKT077 as an upgraded seed for a new round of COMPARE analysis, we identified rhodacyanine FJ5002, a close derivative of MKT077, as the most potent telomerase inhibitor with 50% inhibition at approximately 2 microM. Long-term cultivation of U937, a human leukemia cell line, with subacute concentrations of FJ5002 resulted in population-doubling dependent changes characterized by progressive telomere erosion (from approximately 10 to approximately 4.0 kb), increased chromosome abnormalities, and senescence/crisis-like features. These results indicated that FJ5002 is a genuine and effective antitelomerase agent.
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| Authors | I Naasani, H Seimiya, T Yamori, T Tsuruo |
| Journal | Cancer research (Cancer Res) Vol. 59 Issue 16 Pg. 4004-11 (Aug 15 1999) ISSN: 0008-5472 [Print] United States |
| PMID | 10463599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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