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

Citation
I. Naasani et al., FJ5002: A potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE analysis, CANCER RES, 59(16), 1999, pp. 4004-4011
Citations number
31
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
59
Issue
16
Year of publication
1999
Pages
4004 - 4011
Database
ISI
SICI code
0008-5472(19990815)59:16<4004:FAPTII>2.0.ZU;2-C
Abstract
To facilitate the search for candidate telomerase inhibitors, we exploited the database of the disease-oriented screening program (DOS) available in o ur facility by using COMPARE analysis. In primary and arbitrary screening, we were able to identify the alkaloid berberine as a moderate inhibitor wit h 50% inhibition at similar to 35 mu M. Using this alkaloid as a seed compo und in COMPARE resulted in the identification of other berberine-like compo unds and mitochondria-accumulating agents as highly related to berberine, A mong these compounds, MKT077, a rhodacyanine derivative currently under Pha se I clinical trials, showed a potent inhibitory effect with 50% inhibition at similar to 5 mu M. With MKT077 as an upgraded seed for a new round of C OMPARE analysis, we identified rhodacyanine FJ5002, a close derivative of M KT077, as the most potent telomerase inhibitor with 50% inhibition at simil ar to 2 mu M. Long-term cultivation of U937, a human leukemia cell line, wi th subacute concentrations of FJ5002 resulted in population-doubling depend ent changes characterized by progressive telomere erosion (from similar to 10 to similar to 4.0 kb), increased chromosome abnormalities, and senescenc e/crisis-like features. These results indicated that FJ5002 is a genuine an d effective antitelomerase agent.