CHIR99021 (CT99021), is also known as 6-[[2-[[4-(2,4-Dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl)-2-pyrimidinyl]amino]ethyl]amino]-3-pyridinecarbonitrile and CT99021. It is the most potent and selective inhibitor of GSK3. CHIR99021 is an aminopyrimidine derivative. It inhibits GSK3 Î² and GSK3 Î±. It also functions as a WNT activator. It is the most selective inhibitor of GSK3 reported so far.
Any questions about Inhibitor CHIR99021? See all about it in the post below.What is inhibitor CHIR99021? CHIR99021 (CT99021), is also known as 6-[[2-[[4-(2,4-Dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl)-2-pyrimidinyl]amino]ethyl]amino]-3-pyridinecarbonitrile and CT99021. It is the most potent and selective inhibitor of GSK3. CHIR99021 is an aminopyrimidine derivative. It inhibits GSK3 Î² and GSK3 Î±. It also functions as a WNT activator. It is the most selective inhibitor of GSK3 reported so far. What is the mechanism of action of CHIR99021? CHIR99021 activates Wnt-signaling by binding secreted Wnt-protein to its receptor. Disheveled (Dvl/Dsh) is recruited and inhibits the GSK3 (Glycogen Synthase Kinase 3) located in the beta-catenin destruction complex. This leads to an accumulation of free non-phosphorylated beta-catenin in the cytosol. This then 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. What is Glycogen Synthase Kinase 3 (GSK3)? Glycogen synthase kinase 3 (GSK3) is a conserved signaling molecule. It has essential roles in diverse biological processes. GSK3 activity has been linked to a variety of human diseases. They include diabetes, obesity, inflammation, neurodegenerative and psychiatric disorders. Inhibiting GSK3 activity has become an attractive target to be used in the development of treatment strategies for neurodegenerative and psychiatric disorders. What are Wnt proteins and what is the significance of Wnt proteins and GSK3? Wnt proteins are a family of secreted proteins. They 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 receptors are inhibited, then degradation of Î²-catenin is facilitated via interactions with a protein complex consisting of adenomatous polyposis coli (APC), axin, and GSK3. APC and axin act as scaffold proteins allowing GSK3 to bind and phosphorylate Î²-catenin. They identify it for degradation by the Î²-TrCP€“mediated ubiquitin/proteasome pathway. Are there different types of GSK3 inhibitors? GSK3 inhibitors are of diverse chemotypes and mechanisms of action. The inhibitors include those isolated from natural sources, cations, and synthetic small molecules. Under different mechanism of inhibition, the inhibitors are categorized as ATP-competitive inhibitors, non-ATP- competitive inhibitors, and substrate-competitive inhibitors. What are the different applications of inhibitor CHIR99021?
- Differentiation of cells from human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells.
- Used in maintaining mouse ES cells. Maintains human and mouse hematopoietic stem cells in cytokine-free conditions in combination with rapamycin.
- Enables chemical and lineage reprogramming of various cells.
- 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.
- 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.
- 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.
- 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.