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

• Published in: Molecular pharmacology Vol. 54; no. 1; pp. 1 - 7
• Main Authors: Yonemoto, M, Satoh, T, Arakawa, H, Suzuki-Takahashi, I, Monden, Y, Kodera, T, Tanaka, K, Aoyama, T, Iwasawa, Y, Kamei, T, Nishimura, S, Tomimoto, K
• Format: Journal Article
• Language: English
• Published: United States 01.07.1998
• Subjects: 3T3 Cells - drug effects; 3T3 Cells - metabolism; Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors; Farnesyltranstransferase; Female; Genes, ras - drug effects; Genes, ras - genetics; Genes, ras - physiology; Mice; Mice, Nude; Naphthalenes - chemistry; Naphthalenes - pharmacology; Oxazoles - chemistry; Oxazoles - pharmacology; Polyisoprenyl Phosphates - metabolism; Protein Prenylation - drug effects; Rats; Sesquiterpenes; Subrenal Capsule Assay; Tumor Stem Cell Assay
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.54.1.1

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.