Anti-hormone Therapy

Top Med Chem (2007) 1: 133–168
DOI 10.1007/7355_2006_003
© Springer-Verlag Berlin Heidelberg 2006
Published online: 13 December 2006
Farnesyl Protein Transferase Inhibitors:
Medicinal Chemistry, Molecular Mechanisms,
and Progress in the Clinic
D. W. End 1 ·L.Mevellec 2 ·P.Angibaud 2 (✉)
1 Early Development, Johnson & Johnson Pharmaceutical Research & Development,
Springhouse, PA 19477, USA
2 Department of Medicinal Chemistry,
Johnson & Johnson Pharmaceutical Research & Development,
Campus de Maigremont, BP615, 27106 Val de Reuil, France
pangibau@prdfr.jnj.com
1 Introduction and Historical Overview ..................... 135
2 Biochemistry of Farnesyl Protein Transferase ................ 136
3 Downstream Effectors ............................. 138
3.1 RasProteins ................................... 138
3.2 RhoProteins................................... 141
3.3 NuclearProteinsandG2/MGrowthDelay................... 142
3.4 Upregulation of Transforming Growth Factor β (TGF-β)
ReceptorTypeII(RII) ............................. 144
3.5 Additional Mechanisms:
Rheb,ModulationofSurvival,andHost–TumorInteractions ........ 144
3.6 FTaseKnockoutMice .............................. 146
4 Biomarkers .................................... 146
5 Farnesyl Transferase Inhibitors ........................ 147
5.1 CAAXPeptidomimetics............................. 147
5.2 FPPCompetitiveCompounds ......................... 148
5.3 CAAXPeptideCompetitiveHeterocyclicInhibitors ............. 149
6 Clinical Experience ............................... 157
7 Further Developments ............................. 157
8 Conclusion and Perspectives .......................... 159
References ....................................... 160
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 developed as oral therapeutics. There are now several farnesyl protein inhibitors
(FTIs) in various phases of clinical development and at least two compounds
have entered phase III. The published data suggest some disappointing activity in the
major solid tumors, with more promising activities emerging from studies of hemato-