Laduviglusib (trihydrochloride)

Laduviglusib (CHIR-99021) trihydrochloride is a potent and selective GSK-3α/β inhibitor with IC₅₀s of 10 nM and 6.7 nM. Laduviglusib trihydrochloride shows >500-fold selectivity for GSK-3 over CDC2, ERK2 and other protein kinases. Laduviglusib trihydrochloride is also a potent Wnt/β-catenin signaling pathway activator. Laduviglusib trihydrochloride enhances mouse and human embryonic stem cells self-renewal. Laduviglusib trihydrochloride induces autophagy^[1][2][3]. IC50 & Target: IC50: 10 nM/6.7 nM (GSK-3α/β)^[1] In Vitro: Laduviglusib trihydrochloride inhibits human GSK-3β with K_i values of 9.8 nM^[1]. Laduviglusib trihydrochloride is a small organic molecule that inhibits GSK3α and GSK3β by competing for their ATP-binding sites.In vitro kinase assays reveal that Laduviglusib trihydrochloride specifically inhibits GSK3β (IC₅₀=~5 nM) and GSK3α (IC₅₀=~10 nM), with little effect on other kinases^[4]. In the presence of Laduviglusib trihydrochloride 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 trihydrochloride with an IC₅₀ of 4.9 μM^[2]. In Vivo: In ZDF rats, a single oral dose of Laduviglusib (16 mg/kg or 48 mg/kg) trihydrochloride rapidly lowers plasma glucose, with a maximal reduction of nearly 150 mg/dl 3-4 h after administration^[1]. Laduviglusib (2 mg/kg) trihydrochloride given once, 4 h before irradiation, significantly improves survival after 14.5 Gy abdominal irradiation (ABI). Laduviglusib trihydrochloride treatment significantly blocks crypt apoptosis and accumulation of p-H2AX⁺ cells, and improves crypt regeneration and villus height. Laduviglusib trihydrochloride treatment increases Lgr5⁺ cell survival by blocking apoptosis, and effectively prevents the reduction of Olfm4, Lgr5 and CD44 as early as 4 h^[5].