Synthesis and evaluation of multisubstrate inhibitors of an oncogene-encoded tyrosine-specific protein kinase. 2

Carolyn H. Kruse, Kenneth G. Holden, Priscilla H. Offen, M. Lynn Pritchard, John A. Feild, David J. Rieman, Paul E. Bender, Blair Ferguson, Russell G. Greig, George Poste

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Tyrosine-specific protein kinases that transfer the terminal phosphate from ATP to protein acceptors are associated with certain transforming viruses and cell surface growth factor receptors. Here we describe the synthesis and testing of potential multisubstrate inhibitors of this class of enzymes. The inhibitors were prepared by covalent attachment of the terminal phosphate of ATP or its tetraphosphate analogue to tyrosine mimics. Testing against p60v-abl, the tyrosine kinase from the Abelson murine leukemia virus, showed that the series of inhibitors was moderately potent (IC50 values as low as 13 μM). However, structural modification of the tyrosine mimic, including replacement with a serine-like moiety, had little effect on potency. It is therefore concluded that the ATP moiety is largely responsible for binding and that the enzyme requires additional structural features for recognition of the tyrosine-containing substrate.

Original languageEnglish (US)
Pages (from-to)1768-1772
Number of pages5
JournalJournal of Medicinal Chemistry
Volume31
Issue number9
DOIs
StatePublished - Jan 1 1988
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Kruse, C. H., Holden, K. G., Offen, P. H., Pritchard, M. L., Feild, J. A., Rieman, D. J., Bender, P. E., Ferguson, B., Greig, R. G., & Poste, G. (1988). Synthesis and evaluation of multisubstrate inhibitors of an oncogene-encoded tyrosine-specific protein kinase. 2. Journal of Medicinal Chemistry, 31(9), 1768-1772. https://doi.org/10.1021/jm00117a016