Givinostat (hydrochloride)

Givinostat (ITF-2357) hydrochloride is a HDAC inhibitor with an IC₅₀ of 198 and 157 nM for HDAC1 and HDAC3, respectively. Givinostat hydrochloride can penetrate the blood-brain barrier (BBB).^[1][2][3][4]. IC50 & Target:IC50: 198 nM (HDAC1), 157 nM (HDAC3)^[1], 10 nM (HD2), 7.5 nM (HD1-B), 16 nM (HD1-A)^[3] In Vitro:Givinostat (ITF2357) suppresses total LPS-induced IL-1β production robustly compared with the reduction by ITF3056. At 25, 50, and 100 nM, Givinostat reduces IL-1β secretion more than 70%. Givinostat suppresses the production of IL-6 in PBMCs stimulated with TLR agonists as well as the combination of IL-12 plus IL-18. IL-6 secretion decreases to 50% at 50 nM Givinostat, but at 100 and 200 nM, there is no reduction^[1]. Givinostat (ITF-2357) inhibits JS-1 cell proliferation in a concentration-dependent manner in the CCK-8 assay. Treatment with Givinostat (ITF-2357) ≥500 nM is associated with significant inhibition of JS-1 cell proliferation. Also, the cell inhibition rate significantly differs between the group cotreated with Givinostat (ITF-2357) ≥250 nM plus LPS and the group without LPS treatment^[2]. In Vivo:Givinostat (ITF2357) at 10 mg/kg is used as a positive control and reduces serum TNFα by 60%. Pretreatment of Givinostat (ITF-2357) starting at 0.1 mg/kg significantly reduces the circulating TNFα by nearly 90%. To achieve a significant increase in serum IL-1β production, a higher dose of LPS is injected (10 mg/kg), and blood is collected after 4 h^[1].