TI - GSK-3-selective inhibitors derived from Tyrian purple indirubins . AB - 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 .