FJ5002: a potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE analysis.
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.
Naasani
I
I
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Seimiya
H
H
Yamori
T
T
Tsuruo
T
T
D000970:Antineoplastic Agents / Q000032:analysis* / Q000494:pharmacology*; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000032:analysis / Q000494:pharmacology; D006801:Humans; D011725:Pyridines / Q000032:analysis* / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000032:analysis* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C121172:FJ 5002; D011725:Pyridines; D013844:Thiazoles; C097880:MKT 077; D019098:Telomerase