Abstract
Over a decade has passed since the first report describing farnesyl protein transferase (FTase)and tetrapeptide inhibitors triggered a search for small-molecule inhibitors that could be developedas oral therapeutics. There are now several farnesyl protein inhibitors (FTIs) in various phases of clinicaldevelopment and at least two compounds have entered phase III. The published data suggest some disappointingactivity in the major solid tumors, with more promising activities emerging from studies of hematologicalmalignancies and glioblastoma. The current compounds emerged from various research strategies includingmodeling around the CAAX motif peptide substrate and the farnesyl pyrophosphate (FPP) substrate, as wellas high-throughput screening campaigns. The interaction of inhibitors in the active site of the FT enzymecan be accurately described thanks to the publication of the X-ray structure as well as excellent mechanisticwork. Published structure–activity data have revealed an interesting convergence on imidazole pharmacophores.The original hypothesis that drove development of FTIs anticipated therapy targeted specifically at thefarnesylated Ras oncoproteins and cancers with ras gene mutations. Asexperience with the newer potent FTIs grew, data emerged to suggest that multiple downstream effectors contributeto the antitumor activity of FTIs. The mechanism(s) of action of FTIs and the full therapeutic activityof the class remain areas of active investigation.
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Abbreviations
- AKAP13:
-
A-kinase anchoring protein 13
- AML:
-
Acute myelogenous leukemia
- CENP-E:
-
Centromere-associated protein-E
- CENP-F:
-
Centromere-associated protein-F
- CNS:
-
Central nervous system
- ECG:
-
Electrocardiogram
- FPP:
-
Farnesyl pyrophosphate
- FTase:
-
Farnesyl protein transferase
- FTI:
-
Farnesyl protein transferase inhibitor
- GGTase:
-
Geranylgeranyl protein transferase
- Grb2β:
-
Growth factor receptor binding protein-2β
- GTP:
-
Guanosine triphosphate
- HMGCoA:
-
Hydroxymethylglutaryl-CoA
- H-ras :
-
Harvey ras gene
- N-ras :
-
Neural ras gene
- K-ras :
-
Kirsten ras gene
- HDJ-2:
-
Human DNAJ-2 heat shock protein
- HUVEC:
-
Human umbilical vein endothelial cell
- mTOR:
-
Mammalian target of rapamycin
- NF-κ-B DNA:
-
Nuclear factor kappa B deoxyribonucleic acid
- NMR:
-
Nuclear magnetic resonance
- PI3-kinase/Akt-3:
-
Phosphoinositide-3-kinase/serine–threonine kinase Akt-3
- PGGT:
-
Protein geranylgeranyl transferase
- QTc:
-
Duration of the QT interval corrected for changes in the heart rate
- RabGGTase:
-
Rab geranylgeranyl transferase
- RCE:
-
Ras CAAX endoprotease
- Rheb:
-
Ras homolog enriched in brain
- SAR:
-
Structure–activity relationship
- SH2/SH3:
-
Sequence homology-2/sequence homology-3
- SOS:
-
Son of sevenless
- TGF-β:
-
Transforming growth factor β
- THQ:
-
Tetrahydroquinoline
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Acknowledgments
The authors would like to thank everyone at Johnson & Johnson who has worked on FTIs over the years.
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End, D.W., Mevellec, L., Angibaud, P. (2006). Farnesyl Protein Transferase Inhibitors: Medicinal Chemistry, Molecular Mechanisms, and Progress in the Clinic. In: Bradbury, R.H. (eds) Cancer. Topics in Medicinal Chemistry, vol 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2006_003
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