The DYRKs (dual-specificity tyrosine phosphorylation-regulated kinases) are an evolutionarily conserved family of protein kinases that are found within the CMGC group[3].DYRKs contain a characteristic tyrosine-X-tyrosine (Y-X-Y) residue motif in their activation loop. Phosphorylation of the second tyrosine residue is critical for kinase activity[4]. AZ191 is a potent inhibitor that selectively inhibits DYRK1B with IC50 of 17 nM. Using in vitro kinase assays, phospho-specific immunoblot analysis and MS in conjunction with AZ191, DYRK1B phosphorylates CCND1 at Thr(286), not Thr(288), in vitro and in cells. In HEK (human embryonic kidney)-293 and PANC-1 cells (which exhibit DYRK1B amplification) DYRK1B drives Thr(286) phosphorylation and proteasome-dependent turnover of CCND1 and this is abolished by AZ191 or DYRK1B RNAi.[5]. AZ191 inhibited liposarcoma cell growth, decreased cell motility, and induced apoptosis. Moreover, combined AZ191 with doxorubicin demonstrated an increased anti-cancer effect on liposarcoma cells[6]. Mean inhibitory concentrations (EC50) of 0.98 ± 0.08 μM/SC84227, 0.60 ± 0.02 μM/SC97202, 6.26 ± 1.64 μM/SC97208, 0.71 ± 0.019 μM/Harmine and 0.63 ± 0.23 μM/AZ-191 were determined with human cytomegalovirus strain AD169-GFP for the infection of primary human fibroblasts[7].
AZ191 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Huh7 cells
1 μM
24 h
Evaluate the effect of AZ191 on the cell cycle distribution of Huh7 cells
Cell Death Dis. 2021 Jan 26;12(1):125.
RPE-1
10 μM
1 hour
To investigate the effect of AZ191 on rDNA DSB-induced transcriptional silencing. Results showed that AZ191 pretreatment led to failure of nucleolar transcriptional silencing.
Nucleic Acids Res. 2021 Feb 22;49(3):1485-1496.
HeLa
10 μM
1 hour
To investigate the effect of AZ191 on rDNA DSB-induced transcriptional silencing. Results showed that AZ191 pretreatment led to failure of nucleolar transcriptional silencing.
Nucleic Acids Res. 2021 Feb 22;49(3):1485-1496.
U2OS
10 μM
1 hour
To investigate the effect of AZ191 on rDNA DSB-induced transcriptional silencing. Results showed that AZ191 pretreatment led to failure of nucleolar transcriptional silencing.
Nucleic Acids Res. 2021 Feb 22;49(3):1485-1496.
HEK293 cells
10 μM
10 min
AZ191 failed to inhibit DYRK1B-dependent mTOR-Ser2448 phosphorylation
J Clin Invest. 2022 Feb 1;132(3):e153724.
mKpc4 cells
1 µM
4 days
To evaluate the effect of AZ191 on cell proliferation, results showed that AZ191 treatment increased the percentage of BrDU-positive cells.
Gut. 2024 Sep 9;73(10):1684-1701.
Ciona savignyi embryos
40 µM
4-8 h
To inhibit DYRK1 kinase activity and observe its effects on notochord development and lumenogenesis in ascidian Ciona savignyi. Results showed that AZ191 treatment significantly delayed tail elongation and lumen expansion.
Cells. 2023 Mar 16;12(6):921.
DU145 prostate cancer cells
3–10 µM
1 hour
AZ191 inhibited p27Kip1 nuclear expression, indicating cells were not quiescent
Sci Rep. 2020 Jul 27;10(1):12505.
AZ191 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c nude mice
Subcutaneous xenograft tumor model
Intraperitoneal injection
50 mg/kg
Six injections
Evaluate the inhibitory effect of AZ191 on HCC cell growth
Cell Death Dis. 2021 Jan 26;12(1):125.
Chick embryos
Embryonic chick spinal cord
Injection
600 µg
Single injection, lasting 48 hours
AZ191 increases the numbers of ventral progenitors and MNs by inhibiting endogenous Dyrk1B kinase activity
Cell Mol Life Sci. 2024 Jan 31;81(1):70
Mice
KPC mouse model
Intraperitoneal injection
5 mg/kg
Twice weekly, continuous treatment
To evaluate the effect of AZ191 alone or in combination with other drugs, results showed that AZ191 combination therapy significantly extended the survival of mice.
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