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Farnesyltransferase inhibitors. Preclinical development
1Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. nancy_kohl@merck.com
Abstract:
The Ras proteins are low molecular weight GTP binding proteins that function in the regulation of the transduction of growth proliferative signals from the membrane to the nucleus. Oncogenically mutated ras genes are found in approximately 25% of all human cancers. Localization of the Ras oncoproteins to the inner surface of the plasma membrane is essential for their biological activity. This observation suggested that the enzyme that mediates the membrane localization, farnesyl-protein transferase (FPTase), would be a target for the development of novel anticancer agents. We have developed potent, cell-active inhibitors of FPTase that exhibit antiproliferative activity in cell culture and block the morphologic alterations associated with Ras-induced transformation of mammalian cells in monolayer cultures. In vivo, these compounds block the growth of ras-transformed fibroblasts in a nude mouse xenograft model and block the growth and, in some cases, cause regression of mammary and salivary tumors in several strains of ras transgenic mice in the absence of any detectable side effects. The results of our preclinical studies and those of others suggest that FTIs may have utility against a variety of human cancers, a hypothesis that is currently being tested in the clinic.
Insights
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.