YKL-05-099

YKL-05-099 is a salt-inducible kinase (SIK) inhibitor. YKL-05-099 binds to SIK1 and SIK3 with IC₅₀s of ~10 and ~30 nM, respectively. YKL-05-099 has slightly less potent SIK2-inhibitory (IC₅₀=40 nM)^[1]. IC50 & Target: IC50: 10 nM (SIK1), 30 nM (SIK3), 40 nM (SIK2)^[1] In Vitro: YKL-05-099 has slightly less potent SIK2-inhibitory (IC₅₀=40 nM) and IL-10-enhancing activities (EC₅₀=460 nM). YKL-05-099 binds to SIK1 and SIK3 with IC₅₀s of 10 and 30 nM, respectively, in a competitive binding assay. Preincubating bone marrow-derived macrophages with YKL-05-099 reduces LPS stimulated phosphorylation of HDAC5 at the SIK-specific phosphorylation site Ser259. YKL-05-099 suppresses production of the inflammatory cytokines TNFα, IL-6 and IL-12p40, and only modestly enhances IL-1β release in BMDCs stimulated with the yeast cell wall extract Zymosan A^[1]. In Vivo: YKL-05-099 is non-toxic at concentrations less than 10 μM and stable in mouse liver microsomes for more than 2 hours. YKL-05-099 is highly soluble (PBS solubility=428 μM) and present in an unbound state at appreciable levels in mouse plasma. YKL-05-099 dose dependently decreases phosphorylation of HDAC5 at the SIK-regulated site Ser259; reduced phosphorylation is observed at the lowest dose (5 mg/Kg) and is below the limit of detection by immunoblotting beginning at the 20 mg/Kg dose. YKL-05-099 dose-dependently reduces abundance of TNFα in serum beginning at 5 mg/Kg, and increases IL-10 levels at the 20 mg/Kg dose by more than 2-fold^[1].