CHIR-99021 (CT99021) (Synonyms: CHIR99021, CHIR-99021, CHIR 99021, CT99021,GSK-3 Inhibitor XVI)

CHIR-99021 is the most commonly used GSK-3β inhibitor and is considered the standard small-molecule Wnt agonist.CHIR-99021 is a potent inhibitor with high selectivity^[[1].

CHIR-99021 led to a marked recovery in cell growth and viability suppressed by CDX2 overexpression. CHIR-99021 restored the protein levels of cyclin D1, c-myc, and β-catenin inhibited by overexpression of CDX2, as well as the cell growth and viability^[2].

When the Human Tenon's fibroblasts(HTFs) were treated with TGF-β, a significant increase in the active form of GSK-3β was observed. A significant decrease in the active form of GSK-3β and molecules associated with fibrosis by TGF-β was noted in HTFs treated with CHIR-99021. CHIR-99021 treatment reduced the phosphorylated Smad2/Smad2 and phosphorylated Smad3/Smad3 ratios in HTFs and attenuated HTF migration^[3].

The GSK-3 inhibitor CHIR 99021 trihydrochloride (0–10 mg/kg, ip) was injected 45-min prior to self-administration sessions in a counterbalanced design. After completion of the self-administration dose-effect curve, potential locomotor effects of the GSK-3 inhibitor were assessed. CHIR 99021 (10 mg/kg) dose-dependently increased alcohol reinforced responding with no effect on sucrose self-administration or locomotor activity. CHIR 99021 (10 mg/kg) significantly decreased pGSK-3β expression in all brain regions tested, reduced PICK1 and increased GluA2 total expression only in the NAcb.?Signaling through the GSK-3 / PICK1 / GluA2 molecular pathway drives the positive reinforcing effects of the drug, which are required for abuse liability^[4].

References:
[1].Law SM, Zheng JJ. Premise and peril of Wnt signaling activation through GSK-3β inhibition. iScience. 2022 Mar 25;25(4):104159.
[2].Yu J, Liu D, et al. CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling via transactivation of GSK-3β and Axin2 expression. Cell Death Dis. 2019 Jan 10;10(1):26.?
[3].Lee SY, Chae MK, et al. The Effect of CHIR 99021, a Glycogen Synthase Kinase-3β Inhibitor, on Transforming Growth Factor β-Induced Tenon Fibrosis. Invest Ophthalmol Vis Sci. 2021 Dec 1;62(15):25.
[4].Faccidomo S, Holstein SE, et al. Pharmacological inhibition of glycogen synthase kinase 3 increases operant alcohol self-administration in a manner associated with altered pGSK-3β, protein interacting with C kinase and GluA2 protein expression in the reward pathway of male C57BL/6J mice. Behav Pharmacol. 2020 Feb;31(1):15-26.?