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Research ArticleArticle

J-104,871, a Novel Farnesyltransferase Inhibitor, Blocks Ras Farnesylation In Vivo in a Farnesyl Pyrophosphate-Competitive Manner

Mari Yonemoto, Toshihiko Satoh, Hiroharu Arakawa, Ikuko Suzuki-Takahashi, Yoshiaki Monden, Tsutomu Kodera, Kenji Tanaka, Tetsuya Aoyama, Yoshikazu Iwasawa, Toshio Kamei, Susumu Nishimura and Koji Tomimoto
Molecular Pharmacology July 1998, 54 (1) 1-7; DOI: https://doi.org/10.1124/mol.54.1.1
Mari Yonemoto
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Toshihiko Satoh
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Hiroharu Arakawa
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Ikuko Suzuki-Takahashi
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Yoshiaki Monden
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Tsutomu Kodera
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Kenji Tanaka
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Tetsuya Aoyama
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Yoshikazu Iwasawa
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Toshio Kamei
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Susumu Nishimura
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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Koji Tomimoto
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan
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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 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.

Footnotes

    • Received October 17, 1997.
    • Accepted March 18, 1998.
  • Send reprint requests to: Dr. Mari Yonemoto, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba, 300-2611 Japan. E-mail: yonmtomr{at}banyu.co.jp

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Molecular Pharmacology: 54 (1)
Molecular Pharmacology
Vol. 54, Issue 1
1 Jul 1998
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Research ArticleArticle

J-104,871, a Novel Farnesyltransferase Inhibitor, Blocks Ras Farnesylation In Vivo in a Farnesyl Pyrophosphate-Competitive Manner

Mari Yonemoto, Toshihiko Satoh, Hiroharu Arakawa, Ikuko Suzuki-Takahashi, Yoshiaki Monden, Tsutomu Kodera, Kenji Tanaka, Tetsuya Aoyama, Yoshikazu Iwasawa, Toshio Kamei, Susumu Nishimura and Koji Tomimoto
Molecular Pharmacology July 1, 1998, 54 (1) 1-7; DOI: https://doi.org/10.1124/mol.54.1.1

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Research ArticleArticle

J-104,871, a Novel Farnesyltransferase Inhibitor, Blocks Ras Farnesylation In Vivo in a Farnesyl Pyrophosphate-Competitive Manner

Mari Yonemoto, Toshihiko Satoh, Hiroharu Arakawa, Ikuko Suzuki-Takahashi, Yoshiaki Monden, Tsutomu Kodera, Kenji Tanaka, Tetsuya Aoyama, Yoshikazu Iwasawa, Toshio Kamei, Susumu Nishimura and Koji Tomimoto
Molecular Pharmacology July 1, 1998, 54 (1) 1-7; DOI: https://doi.org/10.1124/mol.54.1.1
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