Benzodiazepine peptidomimetics: Potent inhibitors of ras farnesylation in animal cells

Guy L. James, Joseph L. Goldstein, Michael S. Brown, Thomas E. Rawson, Todd C. Somers, Robert S. McDowell, Craig W. Crowley, Brian K. Lucas, Arthur D. Levinson, James C. Marsters

Research output: Contribution to journalArticle

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Abstract

Oncogenic Ras proteins transform animal cells to a malignant phenotype only when modified by farnesyl residues attached to cysteines near their carboxyl termini. The farnesyltransferase that catalyzes this reaction recognizes tetrapeptides of the sequence CAAX, where C is cysteine, A is an aliphatic amino acid, and X is a carboxyl-terminal methionine or serine. Replacement of the two aliphatic residues with a benzodiazepine-based mimic of a peptide turn generated potent inhibitors of farnesyltransferase [50 percent inhibitory concentration (IC50) < 1 nM]. Unlike tetrapeptides, the benzodiazepine peptidomimetics enter cells and block attachment of farnesyl to Ras, nuclear lamins, and several other proteins. At micromolar concentrations, these inhibitors restored a normal growth pattern to Ras-transformed cells. The benzodiazepine peptidomimetics may be useful in the design of treatments for tumors in which oncogenic Ras proteins contribute to abnormal growth, such as that of the colon, lung, and pancreas.

Original languageEnglish (US)
Pages (from-to)1937-1942
Number of pages6
JournalScience
Volume260
Issue number5116
StatePublished - Jun 25 1993

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Peptidomimetics
Prenylation
Benzodiazepines
Farnesyltranstransferase
ras Proteins
Inhibitory Concentration 50
Cysteine
Lamins
Growth
Methionine
Serine
Pancreas
Colon
Fatty Acids
Phenotype
Amino Acids
Lung
Peptides
Neoplasms
Proteins

ASJC Scopus subject areas

  • General

Cite this

James, G. L., Goldstein, J. L., Brown, M. S., Rawson, T. E., Somers, T. C., McDowell, R. S., ... Marsters, J. C. (1993). Benzodiazepine peptidomimetics: Potent inhibitors of ras farnesylation in animal cells. Science, 260(5116), 1937-1942.

Benzodiazepine peptidomimetics : Potent inhibitors of ras farnesylation in animal cells. / James, Guy L.; Goldstein, Joseph L.; Brown, Michael S.; Rawson, Thomas E.; Somers, Todd C.; McDowell, Robert S.; Crowley, Craig W.; Lucas, Brian K.; Levinson, Arthur D.; Marsters, James C.

In: Science, Vol. 260, No. 5116, 25.06.1993, p. 1937-1942.

Research output: Contribution to journalArticle

James, GL, Goldstein, JL, Brown, MS, Rawson, TE, Somers, TC, McDowell, RS, Crowley, CW, Lucas, BK, Levinson, AD & Marsters, JC 1993, 'Benzodiazepine peptidomimetics: Potent inhibitors of ras farnesylation in animal cells', Science, vol. 260, no. 5116, pp. 1937-1942.
James GL, Goldstein JL, Brown MS, Rawson TE, Somers TC, McDowell RS et al. Benzodiazepine peptidomimetics: Potent inhibitors of ras farnesylation in animal cells. Science. 1993 Jun 25;260(5116):1937-1942.
James, Guy L. ; Goldstein, Joseph L. ; Brown, Michael S. ; Rawson, Thomas E. ; Somers, Todd C. ; McDowell, Robert S. ; Crowley, Craig W. ; Lucas, Brian K. ; Levinson, Arthur D. ; Marsters, James C. / Benzodiazepine peptidomimetics : Potent inhibitors of ras farnesylation in animal cells. In: Science. 1993 ; Vol. 260, No. 5116. pp. 1937-1942.
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