title: Structural bioinformatics-based design of selective, irreversible kinase inhibitors.
abstract: The active sites of 491 human protein kinase domains are highly conserved, which makes the design of selective inhibitors a formidable challenge. We used a structural bioinformatics approach to identify two selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone inhibitor, designed to exploit both selectivity filters, potently and selectively inactivated RSK1 and RSK2 in mammalian cells. Kinases with only one selectivity filter were resistant to the inhibitor, yet they became sensitized after genetic introduction of the second selectivity filter. Thus, two amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity.
authors.affiliation: Program in Chemistry and Chemical Biology, and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-2280, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D019295:Computational Biology; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013912:Threonine / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D006657:Histones; C501112:halomethylketone pyrrolopyrimidine-cmk; C501113:halomethylketone pyrrolopyrimidine-fmk; D013912:Threonine; D012694:Serine; D004815:Epidermal Growth Factor; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D003564:Cytidine Deaminase; D003545:Cysteine