Ro 31-6045, the inactive analogue of the protein kinase C inhibitor Ro 31-8220, blocks in vivo activation of p70(s6k)/p85(s6k): implications for the analysis of S6K signalling

FEBS Lett. 2002 May 22;519(1-3):135-40. doi: 10.1016/s0014-5793(02)02738-2.

Abstract

The mitogen-stimulated protein kinase p70(s6k)/p85(s6k) (S6K) plays an essential role in cell proliferation and growth, with inhibitors of the S6K signalling pathway showing promise as anti-tumour therapeutics. Here, we report that the bisindolylmaleimide derivative Ro 31-6045, previously reported to be inactive as a kinase inhibitor, inhibited S6K activity in vivo with an IC50=8 microM. Structure/function analysis using mutant forms of S6K indicates that Ro 31-6045 inhibition is independent of the upstream activator mTOR. Ro 31-6045 will prove useful in elucidating the complex activation mechanism of S6K and its independence from mTOR will allow confirmation of functional data obtained using the mTOR inhibitor rapamycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Indoles / pharmacology*
  • Isoquinolines / pharmacology
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism
  • Maleimides / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mutagenesis, Site-Directed
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase Inhibitors
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases / antagonists & inhibitors*
  • Ribosomal Protein S6 Kinases / genetics
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides*
  • TOR Serine-Threonine Kinases
  • Transfection

Substances

  • Enzyme Inhibitors
  • Indoles
  • Isoquinolines
  • Maleimides
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Ro 31-6045
  • Sulfonamides
  • H 85
  • Protein Kinases
  • MTOR protein, human
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • TOR Serine-Threonine Kinases
  • Protein Kinase C
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • Sirolimus
  • Ro 31-8220