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Targeting farnesyltransferase for cancer therapy and beyond
Long-Can Mei1, Han Xiao1, Da-Wei Wang1
1State Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China.
Drug Discovery Today
|February 11, 2026
Summary
Next-generation farnesyltransferase inhibitors (FTIs) overcome resistance in Ras-driven cancers by targeting alternative prenylation pathways. These advanced FTIs show promise in combination therapies and diverse disease applications.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Farnesyltransferase (FTase) is crucial for Ras protein activation via prenylation.
- Previous farnesyltransferase inhibitors (FTIs) failed in Ras-driven cancers due to compensatory geranylgeranyltransferase I (GGTase I) activity.
- Ras prenylation is a key step in cell signaling and cancer development.
Purpose of the Study:
- To review recent advances in farnesyltransferase inhibitors (FTIs).
- To explore the success of next-generation FTIs in overcoming resistance mechanisms.
- To discuss the potential of FTIs beyond cancer treatment.
Main Methods:
- Structure-guided drug design.
- Phenotypic screening.
- Computational approaches for drug development.
- Preclinical and clinical studies of FTI combinations.
Main Results:
- Next-generation FTIs exhibit improved selectivity and dual FTase/GGTase I targeting.
- Combinations of FTIs with targeted therapies or immunotherapies demonstrate synergistic antitumor effects.
- FTIs show potential in treating neurodegenerative, infectious, and viral diseases.
Conclusions:
- Modern FTI development strategies have overcome limitations of earlier inhibitors.
- Next-generation FTIs offer a promising therapeutic avenue for Ras-driven cancers.
- FTIs possess broad therapeutic potential across multiple disease areas.
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