GSK-3-selective Inhibitors Derived From Tyrian Purple Indirubins

Chem Biol. 2003 Dec;10(12):1255-66. doi: 10.1016/j.chembiol.2003.11.010.

Abstract

Gastropod mollusks have been used for over 2500 years to produce the "Tyrian purple" dye made famous by the Phoenicians. This dye is constituted of mixed bromine-substituted indigo and indirubin isomers. Among these, the new natural product 6-bromoindirubin and its synthetic, cell-permeable derivative, 6-bromoindirubin-3'-oxime (BIO), display remarkable selective inhibition of glycogen synthase kinase-3 (GSK-3). Cocrystal structure of GSK-3beta/BIO and CDK5/p25/indirubin-3'-oxime were resolved, providing a detailed view of indirubins' interactions within the ATP binding pocket of these kinases. BIO but not 1-methyl-BIO, its kinase inactive analog, also inhibited the phosphorylation on Tyr276/216, a GSK-3alpha/beta activation site. BIO but not 1-methyl-BIO reduced beta-catenin phosphorylation on a GSK-3-specific site in cellular models. BIO but not 1-methyl-BIO closely mimicked Wnt signaling in Xenopus embryos. 6-bromoindirubins thus provide a new scaffold for the development of selective and potent pharmacological inhibitors of GSK-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Embryo, Nonmammalian / drug effects
  • Embryo, Nonmammalian / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / isolation & purification*
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / chemistry
  • Glycogen Synthase Kinase 3 / metabolism
  • Indoles / chemistry
  • Indoles / isolation & purification*
  • Indoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / metabolism
  • Shellfish
  • Signal Transduction / drug effects
  • Substrate Specificity
  • Wnt Proteins
  • Xenopus / embryology
  • Xenopus / metabolism

Substances

  • Enzyme Inhibitors
  • Indoles
  • Proto-Oncogene Proteins
  • Wnt Proteins
  • Glycogen Synthase Kinase 3
  • indirubin