Laduviglusib trihydrochloride (CT99021 trihydrochloride) is a selective glycogen synthase kinase 3 (GSK-3) inhibitor with IC50s of 10 nM and 6.7 nM for GSK-3α and GSK-3β. Laduviglusib trihydrochloride inhibits human GSK-3β with a Ki of 9.8 nM. Laduviglusib trihydrochloride is an activator of Wnt/β-catenin signaling. Laduviglusib trihydrochloride induces autophagy.

GSK-3α:10 nM, GSK-3β:6.7 nM, CDC2:8800 nM

Laduviglusib trihydrochloride(10 μM) lowers the viability of the ES-D3 cells by 24.7% at 2.5 μM, 56.3% at 5 μM, 61.9% at 7.5 μM and 69.2% with an IC50 of 4.9 μM[2]. Laduviglusib trihydrochloride shows >500-fold selectivity over ERK2, CDC2, and other protein kinases. Laduviglusib trihydrochloride specifically inhibits GSK3β and GSK3α with IC50s of 5nM and 10nM in vitro kinase assays[4].

Oral administration of Laduviglusib trihydrochloride(16 mg/kg and 48 mg/kg) rapidly reduces plasma glucose with a maximal reduction of nearly 150 mg/dl in ZDF rats[1]. Laduviglusib trihydrochloride enhances mouse and human embryonic stem cells self-renewal. Laduviglusib trihydrochloride (2 mg/kg) improves survival after 14.5 Gy abdominal irradiation. Laduviglusib trihydrochloride inhibits crypt apoptosis and accumulation of p-H2AX+ cells, and improves crypt regeneration and villus height. Laduviglusib trihydrochloride blocks apoptosis, increases Lgr5+ cell survival and prevents the reduction of Olfm4, Lgr5 and CD44[5].