title: Synthesis and evaluation of multisubstrate inhibitors of an oncogene-encoded tyrosine-specific protein kinase. 1.
abstract: The synthesis and testing of potential multisubstrate inhibitors of tyrosine-specific protein kinases are described. One of the substrates, ATP, was mimicked by the known kinase inhibitor 5'-[4-(fluorosulfonyl)benzoyl]adenosine, which was covalently linked via the sulfonyl moiety to tyrosine mimics. The resulting multisubstrate inhibitors were tested for their ability to inhibit the transfer of phosphate from ATP to a protein acceptor by p60v-abl, the tyrosine kinase encoded by the transforming gene (v-abl) of the Abelson murine leukemia virus (A-MuLV). Although the series of inhibitors displayed moderately potent activity (IC50 values as low as 19 microM), the absence of large effects produced by modification of the tyrosine mimic suggests that they do not behave as multisubstrate inhibitors but bind primarily through the adenosine moiety common to all the inhibitors. This interpretation is strengthened by the finding that the inhibitors lack specificity, inhibiting a serine kinase at comparable concentrations.
authors.affiliation: Department of Medicinal Chemistry, Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101.
authors.forename: C H
authors.initials: CH
authors.lastname: Kruse
authors.forename: K G
authors.initials: KG
authors.lastname: Holden
authors.forename: M L
authors.initials: ML
authors.lastname: Pritchard
authors.forename: J A
authors.initials: JA
authors.lastname: Feild
authors.forename: D J
authors.initials: DJ
authors.lastname: Rieman
authors.forename: R G
authors.initials: RG
authors.lastname: Greig
authors.forename: G
authors.initials: G
authors.lastname: Poste
mesh_terms: D000011:Abelson murine leukemia virus / Q000201:enzymology / Q000235:genetics; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D007700:Kinetics; D009857:Oncogenes; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D014443:Tyrosine; C010959:5'-(4-fluorosulfonylbenzoyl)adenosine; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D000241:Adenosine