The CHIR99021 GSK-3 Inhibitor is both potent and selective.

Small membrane-permeable molecules are widely utilized for maintenance and differentiation of embryonic stem cells (ES) of different species. Glycogen synthase kinase 3 (GSK3) activates the Wnt/beta-catenin pathway when targeted for inhibition.

CHIR99021 GSK-3 Inhibitor

GSK3 is a conserved signaling molecule with essential roles in diverse biological processes. GSK3 activity has been linked to a variety of human diseases including diabetes, obesity, inflammation, neurodegenerative, and psychiatric disorders. Inhibiting GSK3 activity has become an attractive target to be utilized in the development of treatment strategies for neurodegenerative and psychiatric disorders. GSK3 inhibitors possess a diverse range of chemotypes and mechanism of actions. The inhibitors include those isolated from natural sources, cations, and synthetic small molecules.

Under different mechanisms of inhibition, the inhibitors are categorized as ATP-competitive inhibitors, non-ATP-competitive inhibitors, and substrate-competitive inhibitors. Among all the synthetic small molecule GSK3 inhibitors, CHIR 99021 (CT99021) is the most potent and selective inhibitor of GSK3. CHIR 99021 is an aminopyrimidine derivative, inhibiting GSK3 β and GSK3 α as well as functioning as a Wnt activator. It is the most selective inhibitor of GSK3 reported so far.

CHIR99021 GSK-3 Inhibitor

Wnt proteins are a family of secreted proteins that regulate many aspects of cell growth, differentiation, function, and death. Wnt signaling plays an important role in development and maintenance of many organs and tissues, including bone. If Wnts are not expressed or if their binding to receptors is inhibited, degradation of β-catenin is facilitated via interactions with a protein complex consisting of adenomatous polyposis coli (APC), axin, and glycogen synthase kinase 3 (GSK3). APC and axin act as scaffold proteins allowing GSK3 to bind and phosphorylate β-catenin, identifying it for degradation by the β-TrCP mediated ubiquitin/proteasome pathway.

CHIR 99021 activates Wnt-signaling by binding secreted Wnt-protein to its receptor, and disheveled (Dvl/Dsh) is recruited and inhibits the GSK3 located in the beta-catenin destruction complex. This leads to an accumulation of free non-phosphorylated beta-catenin in the cytosol, which translocates to the nucleus and transactivates Wnt-target genes together with the T-cell factor (TCF)/lymphoid-enhancing factor (LEF) family of transcription factors. Thus, chemical inhibition of the GSK3 leads to a pharmacological activation of the canonical Wnt-signaling pathway.

Several studies on mouse and rat ES cells have proved CHIR 99021 to be a potent pharmacological activator of Wnt/beta-catenin pathway. The high potency is combined with very low toxicity, providing a promising future for clinical trials.

Publications

  1. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., and Brivanlou, A.H. (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10: 55-63.
  2. Besser, D. (2004) Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad 2/3. J Biol Chem 279: 45076-45084.
  3. Ying, Q.L., Wray, J., Nichols, J., Batlle-Morera, L., Doble, B., Woodgett, J., Cohen, P., and Smith, A. (2008) The ground state of embryonic stem cell self renewal. Nature 453: 519-523.
  4. Polychronopoulos, P., Magiatis, P., Skaltsounis, A.L., Myrianthopoulos, V., Mikros, E., Tarricone, A., Musacchio, A., Roe, S.M., Pearl, L., Leost, M., Greengard, P., and Meijer, L. (2004) Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J Med Chem 47: 935-946.

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