J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner.
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.
Yonemoto
M
M
Tsukuba Research Institute, Banyu Pharmaceutical, Ltd., Tsukuba, 300-2611 Japan. yonmtomr@banyu.co.jp
Satoh
T
T
Arakawa
H
H
Suzuki-Takahashi
I
I
Monden
Y
Y
Kodera
T
T
Tanaka
K
K
Aoyama
T
T
Iwasawa
Y
Y
Kamei
T
T
Nishimura
S
S
Tomimoto
K
K
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D051231:Farnesyltranstransferase; D005260:Female; D011905:Genes, ras / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D012717:Sesquiterpenes; D013370:Subrenal Capsule Assay; D014410:Tumor Stem Cell Assay
C113495:J 104871; D009281:Naphthalenes; D010080:Oxazoles; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D019883:Alkyl and Aryl Transferases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D051231:Farnesyltranstransferase