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A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity.

Publication ,  Journal Article
Peterson, YK; Kelly, P; Weinbaum, CA; Casey, PJ
Published in: J Biol Chem
May 5, 2006

Inhibiting protein prenylation is an attractive means to modulate cellular processes controlled by a variety of signaling proteins, including oncogenic proteins such as Ras and Rho GTPases. The largest class of prenylated proteins contain a so-called CaaX motif at their carboxyl termini and are subject to a maturation process initiated by the attachment of an isoprenoid lipid by either protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I (GGTase-I). Inhibitors of FTase, termed FTIs, have been the subject of intensive development in the past decade and have shown efficacy in clinical trials. Although GGTase-I inhibitors (GGTIs) have received less attention, accumulating evidence suggests GGTIs may augment therapies using FTIs and could be useful to treat a myriad of additional disease states. Here we describe the characterization of a selective, highly potent, and cell-active GGTase-I inhibitor, GGTI-DU40. Kinetic analysis revealed that inhibition by GGTI-DU40 is competitive with the protein substrate and uncompetitive with the isoprenoid substrate; the Ki for the inhibition is 0.8 nM. GGTI-DU40 is highly selective for GGTase-I both in vitro and in living cells. Studies indicate GGTI-DU40 blocks prenylation of a number of geranylgeranylated CaaX proteins. Treatment of MDA-MB-231 breast cancer cells with GGTI-DU40 inhibited thrombin-induced cell rounding via a process that involves inhibition of Rho proteins without significantly effecting parallel mobilization of calcium via Gbetagamma. These studies establish GGTI-DU40 as a prime tool for interrogating biologies associated with protein geranylgeranylation and define a novel structure for this emerging class of experimental therapeutics.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 5, 2006

Volume

281

Issue

18

Start / End Page

12445 / 12450

Location

United States

Related Subject Headings

  • rap1 GTP-Binding Proteins
  • Signal Transduction
  • Lipids
  • Humans
  • Enzyme Inhibitors
  • Drug Design
  • Dogs
  • Cell Line, Tumor
  • Biochemistry & Molecular Biology
  • Antineoplastic Agents
 

Citation

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Peterson, Y. K., Kelly, P., Weinbaum, C. A., & Casey, P. J. (2006). A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity. J Biol Chem, 281(18), 12445–12450. https://doi.org/10.1074/jbc.M600168200
Peterson, Yuri K., Patrick Kelly, Carolyn A. Weinbaum, and Patrick J. Casey. “A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity.J Biol Chem 281, no. 18 (May 5, 2006): 12445–50. https://doi.org/10.1074/jbc.M600168200.
Peterson YK, Kelly P, Weinbaum CA, Casey PJ. A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity. J Biol Chem. 2006 May 5;281(18):12445–50.
Peterson, Yuri K., et al. “A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity.J Biol Chem, vol. 281, no. 18, May 2006, pp. 12445–50. Pubmed, doi:10.1074/jbc.M600168200.
Peterson YK, Kelly P, Weinbaum CA, Casey PJ. A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity. J Biol Chem. 2006 May 5;281(18):12445–12450.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 5, 2006

Volume

281

Issue

18

Start / End Page

12445 / 12450

Location

United States

Related Subject Headings

  • rap1 GTP-Binding Proteins
  • Signal Transduction
  • Lipids
  • Humans
  • Enzyme Inhibitors
  • Drug Design
  • Dogs
  • Cell Line, Tumor
  • Biochemistry & Molecular Biology
  • Antineoplastic Agents