Inhibition of RAS-targeted prenylation: protein farnesyl transferase inhibitors revisited.
The ras oncogene and its 21 kD protein product, Ras, has emerged during the last decade as a potentially exploitable target for anticancer drug development. The knowledge that Ras was readily prenylated by protein farnesyl transferase (PFTase) and that inhibition of this prenylation had functional consequences for the transformed phenotype that expressed oncogenic Ras provided the rational for the development of PFTase inhibitors. The initial enthusiasm for this approach seemed justified by the early identification of PFTase inhibitors that were able potently and specifically to block Ras processing, signalling and transformation in transformed and tumour cell lines in vitro and in certain selected animal models. More recently the recognition that geranylgeranyl transferase (GGTase) I might also be a therapeutic target is being actively researched. The last couple of years though have proved remarkable with the disclosure of a series of structurally-diverse molecules, whose major in vivo preclinical activites have been well documented against experimental animal tumours, and culminating this year in preliminary reporting of their Phase I clinical evaluations. Nevertheless, during the research and development phases of PFTase inhibitors as pharmaceutical agents for clinical use, there have been several unexpected findings which have raised intriguing and potentially crucial questions about their activities. This review aims to highlight and offer new insights into many of these issues and to bring into perspective concerns arising from basic research, as well as from clinical studies. There seems little doubt that these inhibitors of RAS-targeted prenylation represent a new generation of anticancer drugs for the preclinical researcher, whether they can be successfully exploited in clinical practice should be resolved early in the next millenium.
Hill
B T
BT
Division de Cancérologie Expérimentale I, Centre de Recherche Pierre Fabre, Castres, France. bridget.hill@pierre-fabre.com
Perrin
D
D
Kruczynski
A
A
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006801:Humans; D017368:Protein Prenylation / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins