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 (IC50:40 nM).

SIK1:10 nM, SIK2:40 nM, SIK3:30 nM

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 [1].

YKL-05-099 exhibits high solubility (PBS solubility=428 μM) and is predominantly in an unbound state in mouse plasma, displaying non-toxic characteristics at concentrations below 10 μM. This compound is metabolically stable, showing more than 2 hours of stability in mouse liver microsomes. Functionally, YKL-05-099 effectively modulates immune response by reducing TNFα levels in a dose-dependent manner, starting at 5 mg/Kg, and significantly enhancing IL-10 secretion at a 20 mg/Kg dose, achieving a more than two-fold increase. Furthermore, it inhibits phosphorylation of HDAC5 at the SIK-regulated site (Ser259) in a dose-responsive manner, with notable reduction starting at 5 mg/Kg and becoming undetectable by immunoblotting from the 20 mg/Kg dose onwards [1].