Identification of Ras farnesyltransferase inhibitors by microbial screening.

Hara, M; Akasaka, K; Akinaga, S; Okabe, M; Nakano, H; Gomez, R; Wood, D; Uh, M; Tamanoi, F

doi:10.1073/pnas.90.6.2281

Cited by 257Microbial Natural Products and BiosynthesisProtein Kinase Regulation and GTPase SignalingPlant biochemistry and biosynthesis

Identification of Ras farnesyltransferase inhibitors by microbial screening.

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Hara, M, Akasaka, K, Akinaga, S, Okabe, M, Nakano, H, Gomez, R, Wood, D, Uh, M +1 more·1993·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.90.6.2281PMC PMC46070

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Abstract

A microbial screen using a yeast strain with conditional deficiency in the GPA1 gene was carried out to search for inhibitors of protein farnesyltransferase (PFT). A strain of Streptomyces was found to produce active compounds named UCF1-A, UCF1-B, and UCF1-C. Structural determination of these compounds revealed that UCF1-C is identical to the known antibiotic, manumycin, whereas UCF1-A and UCF1-B are structurally related to manumycin. All three UCF1 compounds suppress the lethality of gpa1 disruption, with UCF1-C exhibiting the strongest activity. UCF1 inhibits yeast as well as rat brain PFT. Fifty percent inhibition of yeast PFT activity is observed with 5 microM UCF1-C. Kinetic analyses of the inhibition suggest that UCF1-C acts as a competitive inhibitor of PFT with respect to farnesyl pyrophosphate, exhibiting a Ki of 1.2 microM, whereas the same compound appears to act as a noncompetitive inhibitor of PFT with respect to the farnesyl acceptor, the Ras protein. UCF1-C shows significant activity to inhibit the growth of Ki-ras-transformed fibrosarcoma, raising the possibility of its use as an antitumor drug.

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Previously reported targets including farnesyltransferase and sphingomyelinase may also play a role in mediating anti-cancer effects or other biological activities.
“Previously reported targets including farnesyltransferase and sphingomyelinase may also play a role in mediating anti-cancer effects or other biological activities 22,23.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [22]
Manumycin A has been shown to inhibit farnesyl transferase activity and sphingomyelinase activity.
“Manumycin A has also been show to inhibit farnesyl transferase activity and sphingomyelinase activity, but asukamycin is not known to inhibit these targets and its anti-cancer mechanism of action is unclear 19–23.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [22]
Asukamycin is not known to inhibit farnesyl transferase or sphingomyelinase and its anti-cancer mechanism of action is unclear.
“Manumycin A has also been show to inhibit farnesyl transferase activity and sphingomyelinase activity, but asukamycin is not known to inhibit these targets and its anti-cancer mechanism of action is unclear 19–23.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [22]

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Methods in yeast genetics
Sherman, F., Fink, G. R., & Hicks, J. B. (1979) · Cold Spring Harbor Laboratory eBooks · Cited by 7,543 · see citing works
<i>ras</i> GENES
Barbacid, M. (1987) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.56.070187.004023 · Cited by 3,885 · see citing works
Inhibition of purified p21 farnesyl:protein transferase by Cys-AAX tetrapeptides
Reiss, Y., Goldstein, J. L., Seabra, M. C., Casey, P. J., & Brown, M. S. (1990) · Cell · doi:10.1016/0092-8674(90)90242-7 · Cited by 817 · see citing works
Sequence dependence of protein isoprenylation
Moores, S. L., Schaber, M. D., Mosser, S. D., Rands, E., O'Hara, M. B., Garsky, V. M., Marshall, M. S., Pompliano, D. L., & Gibbs, W. W. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98729-6 · Cited by 581 · see citing works
Genetic and Pharmacological Suppression of Oncogenic Mutations in RAS Genes of Yeast and Humans
Schafer, W. R., Kim, R., Sterne, R. E., Thorner, J. W., Kim, S., & Rine, J. (1989) · Science · doi:10.1126/science.2569235 · Cited by 530 · see citing works
Ras C-terminal processing enzymes—New drug targets?
Gibbs, W. W. (1991) · Cell · doi:10.1016/0092-8674(91)90352-y · Cited by 454 · see citing works
Protein farnesyltransferase and geranylgeranyltransferase share a common α subunit
Seabra, M. C., Reiss, Y., Casey, P. J., Brown, M. S., & Goldstein, J. L. (1991) · Cell · doi:10.1016/0092-8674(91)90460-g · Cited by 378 · see citing works
GPA1, a haploid-specific essential gene, encodes a yeast homolog of mammalian G protein which may be involved in mating factor signal transduction
Miyajima, I., Nakafuku, M., Nakayama, N., Brenner, C., Miyajima, A., Kaibuchi, K., Arai, K., Kaziro, Y., & Matsumoto, K. (1987) · Cell · doi:10.1016/0092-8674(87)90167-x · Cited by 362 · see citing works
Rab geranylgeranyl transferase. A multisubunit enzyme that prenylates GTP-binding proteins terminating in Cys-X-Cys or Cys-Cys.
Seabra, M. C., Goldstein, J. L., Südhof, T. C., et al. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)49740-8 · Cited by 327 · see citing works
Steady-state kinetic mechanism of ras farnesyl:protein transferase
Pompliano, D. L., Rands, E., Schaber, M. D., Mosser, S. D., Anthony, N. J., & Gibbs, W. W. (1992) · Biochemistry · doi:10.1021/bi00130a010 · Cited by 246 · see citing works
A protein geranylgeranyltransferase from bovine brain: implications for protein prenylation specificity.
Yokoyama, K., Goodwin, G. W., Ghomashchi, F., Glomset, J. A., & Gelb, M. H. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.12.5302 · Cited by 224 · see citing works
Antitumor activity of UCN-01, a selective inhibitor of protein kinase C, in murine and human tumor models.
Akinaga, S., Gomi, K., Morimoto, M., et al. (1991) · PubMed · Cited by 190 · see citing works
Self-citation
Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase
Goldstein, J. L., Brown, M. S., Stradley, S. J., et al. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98441-3 · Cited by 185 · see citing works
Enzymatic Coupling of Cholesterol Intermediates to a Mating Pheromone Precursor and to the Ras Protein
Schafer, W. R., Trueblood, C. E., Yang, C.-C., Mayer, M. P., Rosenberg, S., Poulter, C. D., Kim, S., & Rine, J. (1990) · Science · doi:10.1126/science.2204115 · Cited by 172 · see citing works
Nonidentical subunits of p21H-ras farnesyltransferase. Peptide binding and farnesyl pyrophosphate carrier functions
Reiss, Y., Seabra, M. C., Armstrong, S. A., Slaughter, C. A., Goldstein, J. L., & Brown, M. S. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)99276-8 · Cited by 170 · see citing works
RAM2, an essential gene of yeast, and RAM1 encode the two polypeptide components of the farnesyltransferase that prenylates a-factor and Ras proteins.
He, B., Chen, P., Chen, S. Y., Vancura, K. L., Michaelis, S., & Powers, S. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.24.11373 · Cited by 168 · see citing works
cDNA cloning and expression of the peptide-binding β subunit of rat p21rasfarnesyltransferase, the counterpart of yeast DPR1/RAM1
Chen, W.-J., Andres, D., Goldstein, J. L., et al. (1991) · Cell · doi:10.1016/0092-8674(91)90622-6 · Cited by 167 · see citing works
Mammalian protein geranylgeranyltransferase. Subunit composition and metal requirements.
Moomaw, J. F., & Casey, P. J. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41945-x · Cited by 159 · see citing works
Protein geranylgeranyltransferase of Saccharomyces cerevisiae is specific for Cys-Xaa-Xaa-Leu motif proteins and requires the CDC43 gene product but not the DPR1 gene product.
Finegold, A. A., Johnson, D. I., Farnsworth, C. C., Gelb, M. H., Judd, S. R., Glomset, J. A., & Tamanoi, F. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.10.4448 · Cited by 149 · see citing works
Self-citation
Isoprenoid modification and plasma membrane association: critical factors for ras oncogenicity.
Der, C. J., & Cox, A. D. (1991) · PubMed · Cited by 124 · see citing works
Common Modifications of Trimeric G Proteins and ras Protein: Involvement of Polyisoprenylation
Finegold, A. A., Schafer, W. R., Rine, J., Whiteway, M. S., & Tamanoi, F. (1990) · Science · doi:10.1126/science.1695391 · Cited by 120 · see citing works
Self-citation
Mutants of Saccharomyces cerevisiae defective in the farnesylation of Ras proteins.
Goodman, L., Judd, S. R., Farnsworth, C. C., Powers, S., Gelb, M. H., Glomset, J. A., & Tamanoi, F. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.24.9665 · Cited by 110 · see citing works
Self-citation
Yeast CAL1 is a structural and functional homologue to the DPR1 (RAM) gene involved in ras processing
Ohya, Y., Goebl, M. G., Goodman, L., Petersen‐Bjørn, S., Friesen, J. D., Tamanoi, F., & Anraku, Y. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98904-0 · Cited by 109 · see citing works
Self-citation
Xenopus oocyte germinal-vesicle breakdown induced by [Val12]Ras is inhibited by a cytosol-localized Ras mutant.
Gibbs, W. W., Schaber, M. D., Schofield, T. L., Scolnick, E. M., & Sigal, I. S. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.17.6630 · Cited by 99 · see citing works
Structural homology among mammalian and Saccharomyces cerevisiae isoprenyl-protein transferases.
Kohl, N. E., Diehl, R. E., Schaber, M. D., Rands, E., Soderman, D. D., He, B., Moores, S. L., Pompliano, D. L., Ferro‐Novick, S., & Powers, S. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55146-2 · Cited by 92 · see citing works
The structure of manumycin. I. Characterization, structure elucidation and biological activity.
Zeeck, A., SCHRÖDER, K., Frobel, K., GROTE, R., & Thiericke, R. (1987) · The Journal of Antibiotics · doi:10.7164/antibiotics.40.1530 · Cited by 69 · see citing works
A new antibiotic, asukamycin, produced by Streptomyces.
Ōmura, S., KITAO, C., Tanaka, H., et al. (1976) · The Journal of Antibiotics · doi:10.7164/antibiotics.29.876 · Cited by 56 · see citing works
Purified yeast protein farnesyltransferase is structurally and functionally similar to its mammalian counterpart
Gomez, R. P., Goodman, L., Tripathy, S. K., et al. (1993) · Biochemical Journal · doi:10.1042/bj2890025 · Cited by 56 · see citing works
Self-citation
Mutants of H‐ras that interfere with RAS effector function in Saccharomyces cerevisiae.
Michaeli, T., Field, J. M., Ballester, R., O’Neill, K. E., & Wigler, M. H. (1989) · The EMBO Journal · doi:10.1002/j.1460-2075.1989.tb08454.x · Cited by 49 · see citing works
The structure of manumycin. II. Derivatives.
Zeeck, A., Frobel, K., HEUSEL, C., et al. (1987) · The Journal of Antibiotics · doi:10.7164/antibiotics.40.1541 · Cited by 27 · see citing works
[METABOLITES OF MICROORGANISMS. 41. MANUMYCIN].
Buzzetti, F., Gaeumann, E., Huetter, R., et al. (1963) · PubMed · Cited by 27 · see citing works
Inhibition of farnesyl transferases from malignant and non-malignant cultured human lymphocytes by prenyl substrate analogues
Das, N. P., & Allen, C. M. (1991) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(91)91251-7 · Cited by 18 · see citing works

Flagged first, then by citations

Research works printed but not linked: 5

[7]Goodman, L. E., Judd, S. R., Farnsworth, C. C., Powers, S., Gelb, M. H., Glomset, J. A. & Tamanoi, F. (1990) Proc. Natl. Acad. Sci. USA 87, 9665–9669.
[9]He, B., Chen, P., Chen, S.-Y., Vancura, K. L., Michaelis, S. & Powers, S. (1991) Proc. Natl. Acad. Sci. USA 88, 11373– 11377.
[15]Yokoyama, K., Goodwin, G., Ghomaschchi, F., Glomset, J. A. & Gelb, M. H. (1991) Proc. Natl. Acad. Sci. USA 88, 5302–5306.
[19]Finegold, A. A., Johnson, D. I., Farnsworth, C. C., Gelb, M. H., Judd, S. R., Glomset, J. A. & Tamanoi, F. (1991) Proc. Natl. Acad. Sci. USA 88, 4448–4452.
[28]Gibbs, J. B., Schaber, M. D., Schofield, T. L., Scolnick, E. M. & Sigal, I. S. (1989) Proc. Natl. Acad. Sci. USA 86, 6630-6634.

Sorted by citations

Targeting protein prenylation for cancer therapy
Berndt, N., Hamilton, A. D., & Sebti, S. M. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3151 · Cited by 614 · see citing works
Antitumor compounds from marine actinomycetes
Olano, C., Méndez, C., & Salas, J. A. (2009) · Marine Drugs · doi:10.3390/md7020210 · Cited by 330 · see citing works
Manumycin polyketides act as molecular glues between UBR7 and P53
Isobe, Y., Okumura, M., McGregor, L. M., Brittain, S. M., Jones, M. D., Liang, X., White, R., Forrester, W., McKenna, J. M., Tallarico, J. A., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0557-2 · Cited by 124 · see citing works
The manumycin-group metabolites
Sattler, I., Thiericke, R., & Zeeck, A. (1998) · Natural Product Reports · doi:10.1039/a815221y · Cited by 95 · see citing works
TMC-1 A, B, C and D, New Antibiotics of the Manumycin Group Produced by Streptomyces sp. Taxonomy, Production, Isolation, Physico-chemical Properties, Structure Elucidation and Biological Properties.
KOHNO, J., NISHIO, M., KAWANO, K., NAKANISHI, N., SUZUKI, S.-I., UCHIDA, T., & KOMATSUBARA, S. (1996) · The Journal of Antibiotics · doi:10.7164/antibiotics.49.1212 · Cited by 38 · see citing works
New Type II Manumycins Produced by Streptomyces nodosus ssp. asukaensis and Their Biosynthesis.
HU, Y., & FLOSS, H. G. (2001) · The Journal of Antibiotics · doi:10.7164/antibiotics.54.340 · Cited by 12 · see citing works

J-104,871, a Novel Farnesyltransferase Inhibitor, Blocks Ras Farnesylation In Vivo in a Farnesyl Pyrophosphate-Competitive Manner
Yonemoto, M., Satoh, T., Arakawa, H., Suzuki‐Takahashi, I., Monden, Y., Kodera, T., Tanaka, K., Aoyama, T., Iwasawa, Y., Kamei, T., et al. (1998) · Molecular Pharmacology · doi:10.1124/mol.54.1.1 · Cited by 37 · see citing works
Inhibition of farnesyltransferase with A-176120, a novel and potent farnesyl pyrophosphate analogue
Tahir, S. K., Gu, W., Zhang, H.-C., et al. (2000) · European Journal of Cancer · doi:10.1016/s0959-8049(00)00067-8 · Cited by 17 · see citing works
The beauty in browsing
Dalrymple, T. (2010) · BMJ · doi:10.1136/bmj.c5538
Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase
Manne, V., Ricca, C. S., Brown, J. G., Tuomari, A. V., Yan, N., Patel, D. V., Schmidt, R., Lynch, M. J., Ciosek, C. P., Carboni, J. M., et al. (1995) · Drug Development Research · doi:10.1002/ddr.430340205 · Cited by 69 · see citing works
Combination of the novel farnesyltransferase inhibitor RPR130401 and the geranylgeranyltransferase‐1 inhibitor GGTI‐298 disrupts MAP kinase activation and G1‐S transition in Ki‐Ras‐overexpressing transformed adrenocortical cells
Mazet, J., Padieu, M., Osman‐Ponchet, H., Maume, G., Mailliet, P., Dereu, N. L. M., Hamilton, A. D., Lavelle, F., Sebti, S. M., & Maume, B. F. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01355-1 · Cited by 23 · see citing works

Authors: Hara, M., Akasaka, K., Akinaga, S., Okabe, M., Nakano, H., Gomez, R., Wood, D., Uh, M., & Tamanoi, F.
Affiliations: Kyowa Kirin (Japan) (JP)
ORCID: Nakano, H
Tamanoi, F
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1993-03-15
Volume: 90
Issue: 6
Pages: 2281-2285
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.90.6.2281
PMC: PMC46070
OpenAlex: W2055097128
Cited by: 257
References: 32
Citations by year: 2026: 2 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 6 · 2013: 6 · 2012: 4
FWCI: 14.63
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Cancer Institute (CA 41996, R01CA041996)
Topics: Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
Keywords: manumycin, Streptomyces, competitive inhibition, non-competitive inhibition, Ras proteins, farnesyl pyrophosphate, anticancer agents, microbial screening
MeSH terms: Amino Acid Sequence, Animals, Anti-Bacterial Agents, Antibiotics, Antineoplastic, Brain, Cattle, Cell Transformation, Neoplastic, Fibrosarcoma, Genes, Fungal, Genes, Lethal, Glutathione Transferase, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Molecular Sequence Data, Neoplasm Transplantation, Polyenes, Genes, ras, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Streptomyces, Structure-Activity Relationship, Transferases, Transplantation, Heterologous, Tumor Cells, Cultured, Molecular Structure, Alkyl and Aryl Transferases, Mice, Rats, Polyunsaturated Alkamides

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Identification of Ras farnesyltransferase inhibitors by microbial screening.

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