GSK-3-selective inhibitors derived from Tyrian purple indirubins.
By L. Meijer, A. Skaltsounis, P. Magiatis, P. Polychronopoulos, M. Knockaert, M. Leost, Xiaozhou P. Ryan, Claudia Alin Vonica, Ali H. Brivanlou, R. Dajani and 6 more. Chemistry and Biology, 2003
820 citations recorded by the source corpus.
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.
Subfields: Organic Chemistry
View Paper: https://www.semanticscholar.org/paper/99ed0f03f6a45c197b8fbb1a3312bb996a10464e
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
- D. James
- Ariel J. Levine
- D. Besser
- L. Meijer
- A. Hemmati‐Brivanlou
- N. Sato
- M. Flajolet
- Paul Greengard
Citations in the corpus
- TGFβ/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells (2005, background): “We have previously shown that BIO is also capable of maintaining hESCs in the undifferentiated state, even in the absence of CM, through activation of canonical WNT signaling (Sato et al., 2004; Meijer et al., 2003).”
- Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor (2004, background): “We recently reported the discovery of a new GSK-3 inhibitor, BIO, which is derived from mollusk Tyrian purpl”
- Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration (2009, neutral): “To modulate Wnt activity and PGE2 levels, the GSK3b inhibitor 6-bromoindirubin-30-oxime (BIO, 50 mg/kg) (Meijer et al., 2003), indo (2.”
- A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition (2009, neutral): “TGF-β1 (R&D Systems) was diluted in 4 mM HCl (2 μg ml −1 ) and the GSK-3β inhibitor, BIO-(2´Z, 3´E)-6-bromoindirubin-3´-oxim”
- Pharmacological inhibitors of glycogen synthase kinase 3. (2004, background): “Paullones, especially kenpaullone [29,32], 6-bromo-substituted indirubins [ 20 ,21,33] and the azaindolylmaleimide compound 46 (Figure 2) [29], appear to be among the most selective inhibitors identified so far.”