J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner.

Abstract

Farnesylation of the activated ras oncogene product by protein farnesyltransferase (FTase) is a critical step for its oncogenic function. Because squalene synthase and FTase recruit farnesyl pyrophosphate as a common substrate, we modified squalene synthase (SS) inhibitors to develop FTase inhibitors. Among the compounds tested, a novel FTase inhibitor termed J-104,871 inhibited rat brain FTase with an IC50 of 3.9 nM in the presence of 0.6 microM farnesyl pyrophosphate (FPP), whereas it scarcely inhibited rat brain protein geranylgeranyltransferase-I or SS. The in vitro inhibition of rat brain FTase by J-104,871 depends on the FPP concentration but not on the concentration of Ras peptide. Thus, in vitro studies strongly suggest that J-series compounds have an FPP-competitive nature. J-104,871 also inhibited Ras processing in activated H-ras-transformed NIH3T3 cells with an IC50 value of 3.1 microM. We tested the effects of lovastatin and zaragozic acid A, which modify cellular FPP levels, on Ras processing of J-104,871. Lovastatin, a hepatic hydroxymenthyl coenzyme A reductase inhibitor that reduced the cellular FPP pool, increased the activity of J-104,871, whereas 3 microM zaragozic acid A, an SS inhibitor that raised the FPP level, completely abrogated the activity of J-104,871 even at 100 microM. These results suggest that J-104,871 inhibits FTase in an FPP-competitive manner in whole cells as well as in the in vitro system. Furthermore, J-104,871 suppressed tumor growth in nude mice transplanted with activated H-ras-transformed NIH3T3 cells.

• Authors: M Yonemoto, T Satoh, H Arakawa, I Suzuki-Takahashi, Y Monden, T Kodera, K Tanaka, T Aoyama, Y Iwasawa, T Kamei, S Nishimura, K Tomimoto
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 54 Issue 1 Pg. 1-7 (Jul 1998) ISSN: 0026-895X [Print] United States
• PMID: 9658183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• J 104871
• Naphthalenes
• Oxazoles
• Polyisoprenyl Phosphates
• Sesquiterpenes
• farnesyl pyrophosphate
• Alkyl and Aryl Transferases
• Farnesyl-Diphosphate Farnesyltransferase
• Farnesyltranstransferase

Topics

• 3T3 Cells (drug effects, metabolism)
• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Farnesyl-Diphosphate Farnesyltransferase (antagonists & inhibitors)
• Farnesyltranstransferase
• Female
• Genes, ras (drug effects, genetics, physiology)
• Mice
• Mice, Nude
• Naphthalenes (chemistry, pharmacology)
• Oxazoles (chemistry, pharmacology)
• Polyisoprenyl Phosphates (metabolism)
• Protein Prenylation (drug effects)
• Rats
• Sesquiterpenes
• Subrenal Capsule Assay
• Tumor Stem Cell Assay