GSK3117391

GSK3117391 (ESM-HDAC391; CHR-5154; HDAC-IN-3) is an orally active HDAC inhibitor with a IC₅₀ of 55 nM. Using esterase-sensitive motif technology, GSK3117391 is selectively converted into its active acid metabolite HDAC189 in cells expressing carboxylesterase-1. GSK3117391 induces sustained global protein acetylation in monocytes, inhibits the production of proinflammatory cytokines, depletes circulating monocytes, downregulates the expression of CSF1R, and inhibits monocyte adhesion and differentiation. GSK3117391 can be used in the research of chronic inflammatory diseases^[1]. In Vitro:GSK3117391 potently inhibits class I, class IIb, and class IV HDAC enzymes, and shows no activity against class IIa HDAC enzymes^[1].
GSK3117391 (1.5 nM-10 μM; 4 h) selectively increases global protein acetylation levels in human blood monocytes, with an EC₅₀ of 158 nM, while exerting minimal effects on lymphocytes and granulocytes^[1].
GSK3117391 (1.5 nM-10 μM; overnight) inhibits the production of TNF-α in human whole blood stimulated by LPS (HY-D1056), with an IC₅₀ of 174 nM^[1].
GSK3117391 (10 μM; 1-6 h) rapidly converts to its acidic metabolite HDAC189 in human CD14+ monocytes, and the concentration of HDAC189 increases continuously within 6 hours of incubation^[1].
GSK3117391 (0.01 nM-100 μM; 1-8 h) induces time- and concentration-dependent downregulation of CSF1R expression on human CD14+ monocytes without affecting CCR2 expression^[1].
GSK3117391 (0.51 nM-10 μM; 4-48 h) inhibits M-CSF-induced differentiation of human CD14+ monocytes, with an IC₅₀ value of 118 nM after 4 h of incubation and 19 nM after 20 h of incubation^[1]. In Vivo:ESM-HDAC391 (3-10 mg/kg; i.p.; single dose; two doses 24 hours apart) induces rapid, transient, dose-dependent monocytopaenia and CD115 downregulation in CES1/Es1^elo mice, with maximal 78% to 84% reductions in circulating monocytes observed with 10 mg/kg single or repeat dosing^[1].