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].
YKL-05-099 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Ocy454 cells
0.5 µM
4 hours
Suppressed SOST expression and upregulated RANKL expression
Nat Commun. 2016 Oct 19;7:13176.
Bone marrow macrophages
312 nM
3 days
YKL-05–099 inhibits osteoclast differentiation
Elife. 2021 Jun 23;10:e67772.
Bone marrow macrophages
15 µM
60 minutes
YKL-05–099 blocks M-CSF-induced M-CSFR autophosphorylation and ERK1/2 phosphorylation
Elife. 2021 Jun 23;10:e67772.
LP9 cells
1 µM
72 hours
Evaluate the cytotoxic effect of YKL-05-099 on LP9 cells, results showed lower cytotoxicity when combined with prexasertib in LP9 cells
Oncogenesis. 2022 Apr 20;11(1):18.
BER-DSRCT cells
1 µM
72 hours
Evaluate the cytotoxic effect of YKL-05-099 on DSRCT cells, results showed significant increase in cytotoxicity when combined with prexasertib in BER cells
Oncogenesis. 2022 Apr 20;11(1):18.
JN-DSRCT-1 cells
1 µM
72 hours
Evaluate the cytotoxic effect of YKL-05-099 on DSRCT cells, results showed significant increase in cytotoxicity when combined with prexasertib in JN cells
Oncogenesis. 2022 Apr 20;11(1):18.
YKL-05-099 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
Chow diet-fed
Intraperitoneal injection
10 or 20 mg/kg
Once daily for 10 days
Assess YKL-05-099's promotion of adipose tissue browning, showing upregulated Ucp1, Pgc1a, and Dio2 gene expression in subcutaneous fat and appearance of UCP1-positive adipocytes
Mol Metab. 2023 Aug;74:101753
Mice
Ovariectomy model
Intraperitoneal injection
18 mg/kg
5 times per week for 4 weeks
YKL-05–099 increases bone formation without increasing bone resorption
Elife. 2021 Jun 23;10:e67772.
Mice
Wild-type mice
Intraperitoneal injection
30 mg/kg
Single injection, duration 3 hours
To investigate the effect of YKL-05-099 on the expression of Cyp27b1 and Cyp24a1 genes. Results showed that YKL-05-099 could induce Cyp27b1 expression and suppress Cyp24a1 expression, similar to the actions of PTH.
搜索
