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 develo pment. The knowledge that Ras was readily prenylated by protein farnesyl tr ansferase (PFTase) and that inhibition of this prenylation had functional c onsequences for the transformed phenotype that expressed oncogenic Ras prov ided the rational for the development of PFTase inhibitors. The initial ent husiasm for this approach seemed justified by the early identification of P FTase inhibitors that were able potently and specifically to block Ras proc essing, signalling and transformation in transformed and tumour cell lines in vitro and in certain selected animal models. More recently the recogniti on that geranylgeranyl transferase (GGTase) I might also be a therapeutic t arget is being actively researched. The last couple of years though have pr oved remarkable with the disclosure of a series of structurally-diverse mol ecules, whose major in vivo preclinical activites have been well documented against experimental animal tumours, and culminating this year in prelimin ary reporting of their Phase I clinical evaluations. Nevertheless, during t he research and development phases of PFTase inhibitors as pharmaceutical a gents for clinical use, there have been several unexpected findings which h ave raised intriguing and potentially crucial questions about their activit ies. This review aims to highlight and offer new insights into many of thes e issues and to bring into perspective concerns arising from basic research , as well as from clinical studies. There seems little doubt that these inh ibitors of RAS-targeted prenylation represent a new generation of anticance r drugs for the preclinical researcher, whether they can be successfully ex ploited in clinical practice should be resolved early in the next millenium . (C) 2000 Elsevier Science ireland Ltd. All rights reserved.