CHIR-99021 monohydrochloride

A potent, specific GSK-3 inhibitor with IC50 of 5 nM and 10 nM for GSK3β and GSK3α, respectively; mimics Wnt signaling in preadipocytes, stabilizes free cytosolic beta-catenin and inhibits adipogenesis by blocking induction of C/EBPα and PPARγ; potentiates insulin activation of glucose transport and utilization in vitro and in vivo; also widely used for stem cell differentiation and naive stem cell generation. (In Vitro) :Laduviglusib monohydrochloride inhibits human GSK-3β with Ki values of 9.8 nM. Laduviglusib monohydrochloride is a small organic molecule that inhibits GSK3α and GSK3β by competing for their ATP-binding sites. In vitro kinase assays reveal that Laduviglusib monohydrochloride specifically inhibits GSK3β (IC50=~5 nM) and GSK3α (IC50=~10 nM), with little effect on other kinases. In the presence of Laduviglusib monohydrochloride the viability of the ES-D3 cells is reduced by 24.7% at 2.5 μM, 56.3% at 5 μM, 61.9% at 7.5 μM and 69.2% at 10 μM Laduviglusib monohydrochloride with an IC50 of 4.9 μM. (In Vivo) :In ZDF rats, a single oral dose of Laduviglusib (16 mg/kg or 48 mg/kg) monohydrochloride rapidly lowers plasma glucose, with a maximal reduction of nearly 150 mg/dl 3-4 h after administration. Laduviglusib (2 mg/kg) monohydrochloride given once, 4 h before irradiation, significantly improves survival after 14.5 Gy abdominal irradiation (ABI) . Laduviglusib monohydrochloride treatment significantly blocks crypt apoptosis and accumulation of p-H2AX+ cells, and improves crypt regeneration and villus height. Laduviglusib monohydrochloride treatment increases Lgr5+ cell survival by blocking apoptosis, and effectively prevents the reduction of Olfm4, Lgr5 and CD44 as early as 4 h.