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FJ5002: a potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE
I Naasani1, H Seimiya, T Yamori
1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Cancer Research
|August 27, 1999
Summary
Researchers identified FJ5002, a potent telomerase inhibitor, through COMPARE analysis. This rhodacyanine derivative effectively erodes telomeres and induces senescence in leukemia cells, showing promise as an antitelomerase agent.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Telomerase is a key target for cancer therapy.
- Existing screening methods require optimization for novel inhibitor discovery.
Purpose of the Study:
- To identify novel and potent telomerase inhibitors using computational analysis.
- To evaluate the efficacy of identified compounds in cancer cell models.
Main Methods:
- Utilized COMPARE analysis on a disease-oriented screening program (DOS) database.
- Identified berberine as an initial telomerase inhibitor.
- Iteratively refined seed compounds (MKT077) for enhanced COMPARE analysis.
- Assessed FJ5002's effect on telomere length, chromosomal abnormalities, and senescence in U937 leukemia cells.
Main Results:
- Berberine identified as a moderate telomerase inhibitor (IC50 ≈ 35 µM).
- MKT077, a rhodacyanine derivative, showed potent inhibition (IC50 ≈ 5 µM).
- FJ5002, a close derivative of MKT077, emerged as the most potent inhibitor (IC50 ≈ 2 µM).
- FJ5002 induced significant telomere erosion (approx. 10 kb to 4.0 kb), chromosomal abnormalities, and senescence in U937 cells.
Conclusions:
- FJ5002 is a genuine and effective antitelomerase agent.
- COMPARE analysis is a valuable tool for discovering novel telomerase inhibitors.
- FJ5002 demonstrates potential for development as an anti-cancer therapeutic.