title: BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo.
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 IC(50) 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.
authors.affiliation: MRC Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
authors.forename: Gopal P
authors.initials: GP
authors.lastname: Sapkota
authors.forename: Lorna
authors.initials: L
authors.lastname: Cummings
authors.forename: Felicity S
authors.initials: FS
authors.lastname: Newell
authors.forename: Christopher
authors.initials: C
authors.lastname: Armstrong
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bain
authors.forename: Morten
authors.initials: M
authors.lastname: Frodin
authors.forename: Matthias
authors.initials: M
authors.lastname: Grauert
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Gisela
authors.initials: G
authors.lastname: Schnapp
authors.forename: Martin
authors.initials: M
authors.lastname: Steegmaier
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
mesh_terms: D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009025:Morpholines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011621:Pteridines / Q000494:pharmacology*; D051381:Rats; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C516541:BI D1870; D002867:Chromones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011621:Pteridines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3