AZ505 ditrifluoroacetate demonstrates high selectivity and activity at submicromolar concentrations in vitro. The IC50 of AZ505 ditrifluoroacetate against SMYD2 is 0.12 μM, which is >600-fold higher than its IC50 values against other histone methyltransferases, including SMYD3 (IC50>83.3 μM), DOT1L (IC50>83.3 μM), and EZH2 (IC50>83.3 μM) [1]. AZ505 ditrifluoroacetate functions as a potent and selective inhibitor of SMYD2, with an IC50 of 0.12 μM. The human SMYD (SET and MYND domain-containing protein) family encompasses five members (SMYD1-5). Furthermore, AZ505 ditrifluoroacetate does not inhibit the enzymatic activities of a panel of protein lysine methyltransferases. It is slated for an isothermal titration calorimetry (ITC) binding study, with a Kd of 0.5 μM. In contrast, the calculated Kd for the p53 substrate peptide is 3.7 μM. The binding of AZ505 ditrifluoroacetate to SMYD2 is primarily driven by entropy, indicative of hydrophobic interactions with limited specific hydrogen bonding [2].
体外研究
AZ505 ditrifluoroacetate demonstrates high selectivity and activity at submicromolar concentrations in vitro. The IC50 of AZ505 ditrifluoroacetate against SMYD2 is 0.12 μM, which is >600-fold higher than its IC50 values against other histone methyltransferases, including SMYD3 (IC50>83.3 μM), DOT1L (IC50>83.3 μM), and EZH2 (IC50>83.3 μM) [1].
AZ505 ditrifluoroacetate functions as a potent and selective inhibitor of SMYD2, with an IC50 of 0.12 μM. The human SMYD (SET and MYND domain-containing protein) family encompasses five members (SMYD1-5). Furthermore, AZ505 ditrifluoroacetate does not inhibit the enzymatic activities of a panel of protein lysine methyltransferases. It is slated for an isothermal titration calorimetry (ITC) binding study, with a Kd of 0.5 μM. In contrast, the calculated Kd for the p53 substrate peptide is 3.7 μM. The binding of AZ505 ditrifluoroacetate to SMYD2 is primarily driven by entropy, indicative of hydrophobic interactions with limited specific hydrogen bonding [2].
AZ505 significantly inhibited the proliferation, migration, and invasion ability of SPC-A1 cells
Cell Death Dis. 2021 May 2;12(5):439.
GLC-82 cells
20 µM
24 hours
AZ505 significantly inhibited the proliferation, migration, and invasion ability of GLC-82 cells
Cell Death Dis. 2021 May 2;12(5):439.
MDA-MB231 cells
20 µM
24 hours
Induced cell apoptosis, inhibited cell migration and proliferation
Cell Death Dis. 2018 Feb 27;9(3):326.
HK-2 cells
20 μg/ml
24 hours
To examine the role of SMYD2 in cisplatin-induced AKI, the results showed that SMYD2 siRNA inhibited cisplatin-induced kidney tubular cell injury and apoptosis
Front Pharmacol. 2022 Aug 15;13:829630.
Rat renal interstitial fibroblasts (NRK-49F)
25 µM
36 hours
Inhibited TGF-β1-induced activation of renal interstitial fibroblasts, reduced expression of α-SMA, fibronectin, and collagen I
FASEB J. 2021 Jul;35(7):e21715.
HK-2 cells
100 µg/mL
48 hours
To investigate the effect of COM stimulation on glycolysis in HK-2 cells, the results showed that COM stimulation increased the expression of glycolysis-related enzymes and elevated glycolysis levels
Biomedicines. 2024 Oct 8;12(10):2279.
HaCaT cells
1.2 µM and 12 µM
6 hours
Inhibited BMP2-induced SMAD1/5 phosphorylation
J Biol Chem. 2017 Jul 28;292(30):12702-12712.
AZ505 ditrifluoroacetate 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57/BL6 mice
Cisplatin-induced acute kidney injury model
Intraperitoneal injection
10 mg/kg
Once daily for 48 hours
To investigate the protective effect of AZ505 on cisplatin-induced acute kidney injury, the results showed that AZ505 significantly improved kidney function, attenuated kidney tubular injury and inflammation, and promoted kidney tubular cell proliferation
Front Pharmacol. 2022 Aug 15;13:829630.
C57 black mice
Unilateral ureteral obstruction (UUO) model
Intraperitoneal injection
10 mg/kg
Once daily for 6 days
To evaluate the protective effect of AZ505 on UUO-induced renal fibrosis, results showed that AZ505 significantly reduced ECM deposition and expression of α-SMA, fibronectin, and collagen I
FASEB J. 2021 Jul;35(7):e21715.
C57BL/6 black mice
Calcium oxalate stone mouse model
Intraperitoneal injection
10 mg/kg
Once daily for 12 days
To investigate the effect of AZ505 on glycolysis, kidney injury, and fibrosis in a calcium oxalate stone mouse model, the results showed that AZ505 inhibited glycolysis and alleviated kidney injury and fibrosis
Biomedicines. 2024 Oct 8;12(10):2279.
BALB/c mice
CT26 tumor model
IP injection
20 mg/kg
Every other day from day 4
AZ505 treatment resulted in decreased tumor weight and tumor volume of CT26 cells in BALB/c mice with no decrease in body weight. In vivo flow data showed the increased tumor infiltration of CD8+ T cells.
Sci Adv. 2023 Jun 16;9(24):eade6624
BALB/c Nude mice
Subcutaneous xenograft model
Intraperitoneal injection
40 mg/kg
Once daily for 2 weeks
AZ505 significantly inhibited tumor growth and metastasis
AZ505 significantly attenuated tumor growth in the 786-O cell-implanted nude mice and suppressed Ki67 expression levels in the tumors compared to the control group.
Theranostics. 2019 Oct 22;9(26):8377-8391
Mice
Pkd1nl/nl mouse model
Intraperitoneal injection
5 mg/kg
Once daily for 20 days
To test the effect of AZ505 in delaying cyst growth in a Pkd1 mutant mouse model
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