Elsevier

Seminars in Cancer Biology

Volume 10, Issue 6, December 2000, Pages 443-452
Seminars in Cancer Biology

Regular Article
Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action, and clinical prospects

https://doi.org/10.1006/scbi.2000.0335Get rights and content

Abstract

Farnesyltransferase (FTase) inhibitors are among the current wave of molecularly targeted anti-cancer agents being used to attack malignancy in a rational manner. A large body of preclinical data indicates that FTase inhibitors block cancer cell proliferation through both cytostatic and cytotoxic effects. Interestingly, FTase inhibitors have rather limited effects on normal cell function, suggesting that they may target unique aspects of cancer cell pathophysiology. The development of FTase inhibitors was predicated on the discovery that the Ras oncoproteins must be post-translationally modified to transform cells. However, recent work indicates that the anti-neoplastic effects of FTase inhibitors depend on altering the post-translational modifications of non-Ras proteins as well. In particular, a critical target protein that responds to FTase inhibition by blocking tumor cell growth is RhoB, an endosomal Rho protein that functions in receptor trafficking. In this review, we survey the biological foundations for the clinical development of FTase inhibitors, and consider some of the latest mechanistic studies that reveal how these agents affect cellular physiology.

References (79)

  • L Sepp-Lorenzino et al.

    A farnesyl:protein transferase inhibitor induces p21 expression and G1 block in p53 wild type tumor cells

    J Biol Chem

    (1998)
  • CA Rowell et al.

    Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo

    J Biol Chem

    (1997)
  • A Gampel et al.

    Regulation of epidermal growth factor receptor traffic by the small GTPase RhoB

    Curr Biol

    (1999)
  • P Adamson et al.

    Post-translational modification of p21rho proteins

    J Biol Chem

    (1992)
  • P Lebowitz et al.

    Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB

    J Biol Chem

    (1997)
  • TY Shih et al.

    Characterization of the phosphorylation sites and the surrounding amino acid sequences of the p21 transforming proteins coded for by the Harvey and Kirsten strains of murine sarcoma viruses

    J Biol Chem

    (1982)
  • GC Prendergast

    Farnesyltransferase inhibitors: antineoplastic mechanism and clinical prospects

    Curr Opin Cell Biol

    (2000)
  • V DeVita et al.

    Cancer Principles and Practice of Oncology

    (1997)
  • JL Bos

    Ras gene mutations and human cancer

  • G Bollag et al.

    Regulators and effectors of ras proteins

    Annu Rev Cell Biol

    (1991)
  • D Lowy et al.

    Regulators and effectors of Ras

    Annu Rev Biochem

    (1993)
  • GJ Clarke et al.

    Ras proto-oncogene activation in human malignancy

  • R Mangues et al.

    Tumorigenesis and male sterility in transgenic mice expressing a MMTV/N-ras oncogene

    Oncogene

    (1990)
  • S Shirasawa et al.

    Altered growth of human colon cancer cell lines disrupted at activated Ki-Ras

    Science

    (1993)
  • L AT Chin

    Essential role for oncogenic Ras in tumour maintenance

    Nature

    (1999)
  • TY Shih et al.

    Guanine nucleotide-binding and autophosphorylating activites assocated with the p21src protein of Harvey murine sarcoma virus

    Nature

    (1980)
  • P Chardin et al.

    Human SOS1: a guanine nucleotide exchange factor for Ras that binds to GRB2

    Science

    (1993)
  • JB Gibbs et al.

    The potential of farnesyltransferase inhibitors as cancer chemotherapeutics

    Annu Rev Pharmacol Toxicol

    (1997)
  • K Kato et al.

    Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity

    Proc Natl Acad Sci USA

    (1992)
  • CA Omer et al.

    Characterization of recombinant human farnesyl-protein transferase: cloning, expression, farnesyl diphosphate binding and functional homology with yeast prenyl-protein transferases

    Biochemistry

    (1993)
  • EC Lerner et al.

    Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase-I inhibitor in human tumor cell lines

    Oncogene

    (1997)
  • J Sun et al.

    Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts

    Oncogene

    (1998)
  • AD Cox et al.

    Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras function

    Mol Cell Biol

    (1992)
  • DM Leonard

    Ras farnesyltransferase: a new therapeutic target

    J Med Chem

    (1997)
  • M Hara et al.

    Identification of Ras farnesyltransferase inhibitors by microbial screening

    Proc Natl Acad Sci USA

    (1993)
  • RB Lingham et al.

    Chaetomella acutiseta produces chaetomellic acids A and B which are reversible inhibitors of farnesyl-protein transferase

    Appl Microbiol Biotechnol

    (1993)
  • SL Graham

    Pseudopeptide inhibitors of Ras farensyl-protein transferase

    J Med Chem

    (1994)
  • DJ Augeri

    Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase

    J Med Chem

    (1998)
  • TM Williams

    2-substituted piperazines as constrained amino acids: application to the synthesis of potent, non-carboxylic acid inhibitors of farnesyltransferase

    J Med Chem

    (1996)

    • Cited by (71)

    View all citing articles on Scopus
    1

    Email: [email protected]

    View full text
    Copyright © 2000 Academic Press. All rights reserved.