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[Cancer Research 59, 4004-4011, August 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 4004-4011, August 15, 1999]
© 1999 American Association for Cancer Research

Experimental Therapeutics

FJ5002: A Potent Telomerase Inhibitor Identified by Exploiting the Disease-oriented Screening Program with COMPARE Analysis1

Imad Naasani2, Hiroyuki Seimiya, Takao Yamori and Takashi Tsuruo

Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455 [I. N., H. S., T. Y., T. T.], and Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032 [I. N., T. T.], Japan

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 ~35 µM. 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 ~5 µM. 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 ~2 µM. 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 ~10 to ~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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Copyright © 1999 by the American Association for Cancer Research.