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Farnesyltransferase inhibitors. Preclinical development.
1Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. nancy_kohl@merck.com
Annals of the New York Academy of Sciences
|February 10, 2000
Summary
Novel farnesyl-protein transferase inhibitors (FTIs) show potent anticancer activity by blocking Ras oncoprotein localization. These FTI compounds effectively inhibit tumor growth in preclinical models, suggesting their potential for treating various human cancers.
Area of Science:
- Molecular Biology
- Oncology
- Drug Discovery
Background:
- Ras proteins are key regulators of cell growth signals.
- Mutated ras genes are implicated in approximately 25% of human cancers.
- Ras oncoprotein localization to the plasma membrane is crucial for its activity.
Purpose of the Study:
- To develop novel anticancer agents targeting farnesyl-protein transferase (FPTase).
- To evaluate the efficacy of FPTase inhibitors (FTIs) in preclinical cancer models.
Main Methods:
- Development of potent, cell-active FPTase inhibitors.
- Assessment of antiproliferative activity in cell culture.
- Evaluation in vivo using a nude mouse xenograft model and ras transgenic mice.
Main Results:
- Developed FTIs demonstrated antiproliferative effects in cell culture.
- Inhibitors blocked Ras-induced transformation of mammalian cells.
- In vivo studies showed blockade of tumor growth and regression of existing tumors without detectable side effects.
Conclusions:
- Farnesyl-protein transferase inhibitors show significant promise as anticancer agents.
- Preclinical data suggest FTIs may be effective against a range of human cancers.
- Clinical trials are underway to test the therapeutic utility of FTIs.