Development of farnesyl transferase inhibitors: a review

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Farnesyl transferase inhibitors (FTIs) represent a novel class of anticancer agents targeting protein farnesylation.
• FTIs are believed to inhibit Ras activation, leading to cell growth arrest, with potent preclinical activity.
• Despite promising preclinical data, FTIs have shown limited efficacy in clinical trials, suggesting issues in their development.

Purpose of the Study:

• To propose and review an algorithm for developing biologically active anticancer drugs.
• To analyze the development of FTIs using this algorithm, identifying underestimated steps.
• To enhance the success rate of future anticancer drug development.

Main Methods:

• Review of farnesyl transferase inhibitor development from discovery to clinical trials.
• Analysis of drug development process against a proposed algorithm.
• Examination of molecular biology of Ras activation and alternative pathways like geranylgeranylation.

Main Results:

• Underestimation of molecular biology: focus on H-Ras activation overlooked K-Ras and other farnesylated proteins' roles in tumorigenesis.
• Inhibition of farnesylation may be insufficient; geranylgeranylation can activate K-Ras, counteracting FTI effects.
• Lack of a well-defined proof of concept in both preclinical and clinical studies was identified.

Conclusions:

• The development of FTIs highlights critical underestimations in understanding molecular pathways and achieving robust proof of concept.
• Future biologically active anticancer drug development should integrate the proposed algorithm to improve clinical success rates.
• A comprehensive understanding of target pathways and rigorous validation are crucial for translating preclinical promise into clinical benefit.