AGK2 acts as a selective inhibitor for SIRT2, demonstrating an IC50 value of 3.5 μM. It also inhibits SIRT1 and SIRT3, with respective IC50 values of 30 μM and 91 μM[1]. AGK2 markedly suppresses cell multiplication in correlation with the dosage. Additionally, AGK2 curtails cell expansion dose-dependently while not triggering cytotoxic effects at lower concentrations. Following a 12-day period of AGK2 treatment at 5 μM, there is a notable decline in the colony-forming capability of cells in soft agar to 46% compared to control cells. Western blot results indicate a dose-dependent reduction in the levels of CDK4, CDK6, and cyclin D1 post-AGK2 treatment. AGK2 also downregulates the expression of the p53 protein[2]. Exposing microglial BV2 cells to AGK2 at a concentration of 10 μM results in a considerable elevation of PAR signals. This treatment also causes a notable reduction in intracellular ATP levels and a significant rise in both advanced apoptosis and cell necrosis[3].
To assess the expression of CCL17 and alternative activation markers
JCI Insight. 2019 Feb 21;4(4):e124710.
HCCLM3 and SMMC-7721 cells
20 µM
8 hours
To enhance FGL1 acetylation and reduce its protein levels.
J Clin Invest. 2023 May 1;133(9):e164528.
AGK2 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
ICR mice
Busulfan-induced non-obstructive azoospermic mouse model
Intraperitoneal injection
1 mg/kg
Daily for five weeks
To investigate the effect of AGK2 on the protective role of Npre in promoting spermatogenesis and alleviating ferroptosis in BU-treated mice. The results showed that AGK2 injection almost abolished the recovery effect of Npre on SIRT2 level, sperm concentration, and motility, and mitigated the protective effects of Npre on ferroptosis and spermatogenesis.
Theranostics. 2024 Apr 15;14(6):2622-2636
C57Bl/6J mice
NAFLD model
Intraperitoneal injection
1 mg/kg/day
Once daily for two weeks
To test whether inhibition of SIRT2 affects the NR-induced anti-NAFLD effects in mice. The results showed that AGK2 treatment significantly compromised the therapeutic effects of NR on NAFLD, including improvements in hepatic steatosis, inflammation, and fibrosis.
Theranostics. 2021 Feb 25;11(9):4381-4402
C57BL/6 mice and BALB/c mice
Hepa 1-6 and H22 syngeneic cancer models
Intraperitoneal injection
10 mg/kg
Three times a week
To suppress tumor growth and enhance the therapeutic effect of PD-L1 blockade.
J Clin Invest. 2023 May 1;133(9):e164528.
Mice
Allergic asthma model
Intraperitoneal injection
10 mg/kg
Days 12, 13, and 14, administered 30 minutes prior to DRA challenge
To attenuate allergic inflammation by modulating alternative activation of macrophages and CCL17 production
JCI Insight. 2019 Feb 21;4(4):e124710.
C57BL/6 mice
HSV-1 infection model
Intraperitoneal injection
40 mg/kg
1 day before and 1 day after HSV-1 infection
AGK2 pretreatment significantly reduced HSV-1 RNA levels in the blood, brain, and liver tissues of mice and increased IFN-β production.
EMBO Rep. 2023 Dec 6;24(12):e57500
C57BL/6 mice
DSS-induced colitis
Intraperitoneal injection
50 mg/kg
Three times via intraperitoneal (IP) injection
AGK2 showed protection in the IBD mouse model
Proc Natl Acad Sci U S A. 2024 Apr 30;121(18):e2319833121
AGK2 动物研究
Animal study
AGK2 notably decreases mortality and cytokine levels in the blood, including TNF-α and IL-6. Furthermore, AGK2 reduces the production of TNF-α and IL-6 in cultured splenocytes[4].
Inhibition of full length human SIRT2 expressed in Escherichia coli BL21 (DE3) cells using fluorogenic 7-amino-4-methylcoumarin (AMC)-labeled peptide by fluorescence assay, IC50=1.56 μM
25275824
H4 cells
Function assay
24 h
Inhibition of SIRT2 in H4 cells co-transfected with alphaSyn and synphilin1 assessed as enlarged alphaSyn inclusions after 24 hrs
17588900
HeLa cells
Function assay
Inhibition of over-expressed SIRT2 immunoprecipitated from HeLa cells transfected with SIRT2-myc expression construct
17588900
human 30P cells
Cytotoxic assay
72 h
Cytotoxicity against human 30P cells after 72 hrs by celltiter-glo luminescent assay, CC50=12.5 μM
23189967
human 30PT cells
Cytotoxic assay
72 h
Cytotoxicity against human 30PT cells after 72 hrs by Cell-titer GLo assay, CC50=9.6 μM
22931526
human HCT116 cells
10 μM
Function assay
8 h
Inhibition of SIRT2 in human HCT116 cells assessed as increase in acetylated alpha-tubulin at 10 uM after 8 hrs by Western blot analysis
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