BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo

Gopal P. Sapkota, Lorna Cummings, Felicity S. Newell, Christopher Armstrong, Jennifer Bain, Morten Frodin, Matthias Grauert, Matthias Hoffmann, Gisela Schnapp, Martin Steegmaier, Philip Cohen, Dario R. Alessi

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    Abstract

    Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of PKA, protein kinase B (also known as Akt), PKC, S6K p70 (ribosomal S6 kinase), RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated protein kinase), which then mediate many of the physiological processes that are regulated by these extracellular agonists. It can be difficult to assess the individual functions of each AGC kinase because their substrate specificities are similar. Here we describe the small molecule BI-D1870, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC50 of 10-30 nM, but does not signi-ficantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. In contrast, BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester- or EGF-induced phosphorylation of CREB (cAMP-response-element-binding protein), consistent with the genetic evidence indicating that MSK, and not RSK, isoforms mediate the mitogen-induced phosphorylation of this transcription factor.

    Original languageEnglish
    Pages (from-to)29-38
    Number of pages10
    JournalBiochemical Journal
    Volume401
    Issue number1
    DOIs
    Publication statusPublished - 16 Oct 2007

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    90-kDa Ribosomal Protein S6 Kinases
    Phosphorylation
    Protein Isoforms
    Protein Kinases
    Ribosomal Protein S6 Kinases
    Phosphotransferases
    Phorbol Esters
    Mitogens
    Epidermal Growth Factor
    Physiological Phenomena
    70-kDa Ribosomal Protein S6 Kinases
    Glycogen Synthase Kinases
    Cyclic AMP Response Element-Binding Protein
    Proto-Oncogene Proteins c-akt
    Hormones
    Substrates
    Heat-Shock Proteins
    Substrate Specificity
    Mitogen-Activated Protein Kinases
    Inhibitory Concentration 50

    Cite this

    Sapkota, Gopal P. ; Cummings, Lorna ; Newell, Felicity S. ; Armstrong, Christopher ; Bain, Jennifer ; Frodin, Morten ; Grauert, Matthias ; Hoffmann, Matthias ; Schnapp, Gisela ; Steegmaier, Martin ; Cohen, Philip ; Alessi, Dario R. / BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. In: Biochemical Journal. 2007 ; Vol. 401, No. 1. pp. 29-38.
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    abstract = "Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of PKA, protein kinase B (also known as Akt), PKC, S6K p70 (ribosomal S6 kinase), RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated protein kinase), which then mediate many of the physiological processes that are regulated by these extracellular agonists. It can be difficult to assess the individual functions of each AGC kinase because their substrate specificities are similar. Here we describe the small molecule BI-D1870, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC50 of 10-30 nM, but does not signi-ficantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. In contrast, BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester- or EGF-induced phosphorylation of CREB (cAMP-response-element-binding protein), consistent with the genetic evidence indicating that MSK, and not RSK, isoforms mediate the mitogen-induced phosphorylation of this transcription factor.",
    author = "Sapkota, {Gopal P.} and Lorna Cummings and Newell, {Felicity S.} and Christopher Armstrong and Jennifer Bain and Morten Frodin and Matthias Grauert and Matthias Hoffmann and Gisela Schnapp and Martin Steegmaier and Philip Cohen and Alessi, {Dario R.}",
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    Sapkota, GP, Cummings, L, Newell, FS, Armstrong, C, Bain, J, Frodin, M, Grauert, M, Hoffmann, M, Schnapp, G, Steegmaier, M, Cohen, P & Alessi, DR 2007, 'BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo', Biochemical Journal, vol. 401, no. 1, pp. 29-38. https://doi.org/10.1042/BJ20061088

    BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. / Sapkota, Gopal P.; Cummings, Lorna; Newell, Felicity S.; Armstrong, Christopher; Bain, Jennifer; Frodin, Morten; Grauert, Matthias; Hoffmann, Matthias; Schnapp, Gisela; Steegmaier, Martin; Cohen, Philip; Alessi, Dario R.

    In: Biochemical Journal, Vol. 401, No. 1, 16.10.2007, p. 29-38.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo

    AU - Sapkota, Gopal P.

    AU - Cummings, Lorna

    AU - Newell, Felicity S.

    AU - Armstrong, Christopher

    AU - Bain, Jennifer

    AU - Frodin, Morten

    AU - Grauert, Matthias

    AU - Hoffmann, Matthias

    AU - Schnapp, Gisela

    AU - Steegmaier, Martin

    AU - Cohen, Philip

    AU - Alessi, Dario R.

    PY - 2007/10/16

    Y1 - 2007/10/16

    N2 - Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of PKA, protein kinase B (also known as Akt), PKC, S6K p70 (ribosomal S6 kinase), RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated protein kinase), which then mediate many of the physiological processes that are regulated by these extracellular agonists. It can be difficult to assess the individual functions of each AGC kinase because their substrate specificities are similar. Here we describe the small molecule BI-D1870, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC50 of 10-30 nM, but does not signi-ficantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. In contrast, BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester- or EGF-induced phosphorylation of CREB (cAMP-response-element-binding protein), consistent with the genetic evidence indicating that MSK, and not RSK, isoforms mediate the mitogen-induced phosphorylation of this transcription factor.

    AB - Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of PKA, protein kinase B (also known as Akt), PKC, S6K p70 (ribosomal S6 kinase), RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated protein kinase), which then mediate many of the physiological processes that are regulated by these extracellular agonists. It can be difficult to assess the individual functions of each AGC kinase because their substrate specificities are similar. Here we describe the small molecule BI-D1870, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC50 of 10-30 nM, but does not signi-ficantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. In contrast, BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester- or EGF-induced phosphorylation of CREB (cAMP-response-element-binding protein), consistent with the genetic evidence indicating that MSK, and not RSK, isoforms mediate the mitogen-induced phosphorylation of this transcription factor.

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    DO - 10.1042/BJ20061088

    M3 - Article

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