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Inactivation of protein farnesyltransferase by active-site-targeted dicarbonyl compounds

K J Okolotowicz1, W J Lee, R F Hartman

  • 1Department of Chemistry and Biochemistry, PO Box 871604, Arizona State University, Tempe, AZ 85287-1604, USA.

Archiv Der Pharmazie
|July 31, 2001
PubMed

Insights

Alpha-dicarbonyl compounds effectively inhibit protein farnesyltransferase (FTase) activity in vitro. These compounds show potential as chemotherapeutic agents by blocking farnesylation, a key process in cancer cell proliferation.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Protein farnesylation by FTase is crucial for cellular compartmentalization.
  • Mutant Ras protein localization is essential for cancer cell proliferation.

Purpose of the Study:

  • To investigate the inhibitory effects of alpha-dicarbonyl compounds on FTase activity.
  • To explore the potential of these compounds as chemotherapeutic agents.

Main Methods:

  • In vitro assays using human recombinant FTase and a Ras model peptide.
  • Testing various alpha-dicarbonyl compounds, including isoprenoid-derived diketones.

Main Results:

  • Isoprenoid-derived diketones potently inhibited FTase activity in a dose- and time-dependent manner.
  • Several other alpha-dicarbonyl compounds also demonstrated significant FTase inhibition.
  • Higher concentrations led to more rapid and extensive inactivation of FTase.

Conclusions:

  • Alpha-dicarbonyl compounds effectively interfere with protein farnesylation.
  • These compounds may serve as a basis for developing novel chemotherapeutic agents targeting FTase.

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