Salt-inducible kinase (SIK), which belongs to the sucrose non-fermenting 1/AMP-activated protein kinase family, was first discovered in the adrenal cortex of a rat on a high-salt diet[2]. SIK1 has a role in the fine tuning of steroidogenic enzyme production during the initial phase of steroidogenesis. SIK2 is found in adipocytes and phosphorylates a specific serine residue in insulin receptor substrate-1[3]. YKL-05-099 is an inhibitor of the salt-inducible kinase(SIK1 and SIK3 ; IC50s: 10 and 30 nM, respectively). It has a slightly less potent SIK2-inhibitory (IC50:40nM). YKL-05-099 inhibits the 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. 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 (IC50s: 10 and 30 nM, respectively, in a competitive binding assay). Preincubating bone marrow-derived macrophages with YKL-05-099 decreases LPS stimulated phosphorylation of HDAC5 at the SIK-specific phosphorylation site Ser259. 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 is non-toxic at concentrations of less than 10 μM and stable in mouse liver microsomes for more than 2 hours. YKL-05-099 dose-dependently decreases the 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. 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[4].
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