FJ5002 : A potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE analysis

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 16; pp. 4004 - 4011
• Main Authors: NAASANI, I, SEIMIYA, H, YAMORI, T, TSURUO, T
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.1999
• Subjects: alkaloids; Antineoplastic Agents - analysis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Databases, Factual; Drug Screening Assays, Antitumor; Enzyme Inhibitors - analysis; Enzyme Inhibitors - pharmacology; General pharmacology; Humans; Medical sciences; mitochondria-accumulating agents; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Pyridines - analysis; Pyridines - pharmacology; Telomerase - antagonists & inhibitors; telomerase inhibitors; Thiazoles - analysis; Thiazoles - pharmacology; Human; RNA-directed DNA polymerase; Enzyme; Transferases; Enzyme inhibitor; Malignant hemopathy; Screening test; In vitro; Biological activity; Screening; Nucleotidyltransferases; Chronic; Structure activity relation; Lymphoproliferative syndrome; Established cell line; Tumor cell; Prolymphocytic leukemia
• ISSN: 0008-5472; 1538-7445

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.