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Cancer pp 133-168 | Cite as

Farnesyl Protein Transferase Inhibitors: Medicinal Chemistry, Molecular Mechanisms, and Progress in the Clinic

Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 1)

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.

Farnesyl transferase inhibitor Protein prenylation Ras protein Acute myeloid leukemia 

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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Notes

Acknowledgments

The authors would like to thank everyone at Johnson & Johnson who has worked on FTIs over the years.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  1. 1.Early DevelopmentJohnson & Johnson Pharmaceutical Research & DevelopmentSpringhouseUSA
  2. 2.Department of Medicinal ChemistryJohnson & Johnson Pharmaceutical Research & DevelopmentVal de ReuilFrance

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