TY - JOUR T1 - J-104,871, a Novel Farnesyltransferase Inhibitor, Blocks Ras Farnesylation <em>In Vivo</em> in a Farnesyl Pyrophosphate-Competitive Manner JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1 LP - 7 DO - 10.1124/mol.54.1.1 VL - 54 IS - 1 AU - Mari Yonemoto AU - Toshihiko Satoh AU - Hiroharu Arakawa AU - Ikuko Suzuki-Takahashi AU - Yoshiaki Monden AU - Tsutomu Kodera AU - Kenji Tanaka AU - Tetsuya Aoyama AU - Yoshikazu Iwasawa AU - Toshio Kamei AU - Susumu Nishimura AU - Koji Tomimoto Y1 - 1998/07/01 UR - http://molpharm.aspetjournals.org/content/54/1/1.abstract N2 - 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 μm 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 μm. 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 μmzaragozic acid A, an SS inhibitor that raised the FPP level, completely abrogated the activity of J-104,871 even at 100 μm. 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. ER -