PDHK (pyruvate dehydrogenase kinase) is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP. AZD7545 is a novel PDHK inhibitor with IC50 values of 36.8nM/6.4nM for PDHK1/2[3], and EC50 value of 5.2nM for increasing PDH activity. It stimulated the rate of pyruvate oxidation with EC50 value of 105nM in rat hepatocytes. A single dose of AZD7545 to Wistar rats increased the proportion of liver PDH in its active, dephosphorylated form in a dose-related manner from 24.7 to 70.3% at 30 mg/kg; and in skeletal muscle from 21.1 to 53.3%. A single dose of 10 mg/kg also significantly elevated muscle PDH activity in obese Zucker (fa/fa) rats. AZD7545 (10 mg/kg) twice daily for 7 days markedly improved the 24-h glucose profile, by eliminating the postprandial elevation in blood glucose[4]. AZD7545 failed to inhibit PDHK4 and paradoxically, at higher concentrations (>10 nM), AZD7545 stimulated PDHK4 activity[3].
作用机制
AZD7545 docks into the lipoamide-binding site on PDHK2 thus inhibiting interaction with the E2 subunit. It inhibits PDHK in a non-ATP competitive manner.[3]
AZD7545 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SKMel30
10 μM
120 h
Inhibition of PDK1 leads to growth suppression of NRAS mutant cells
Mol Cancer. 2017 Jun 8;16(1):102.
501Mel
10 μM
90 h
Inhibition of PDK1 leads to growth suppression of BRAFV600E mutant cells
Mol Cancer. 2017 Jun 8;16(1):102.
IGR37
10 μM
90 h
Inhibition of PDK1 leads to growth suppression of BRAFV600E mutant cells
Mol Cancer. 2017 Jun 8;16(1):102.
A375
10 μM
90 h
Inhibition of PDK1 leads to growth suppression of BRAFV600E mutant cells
Mol Cancer. 2017 Jun 8;16(1):102.
PDK3
50 nM
30 min
Determination of IC50 for AZD7545 on PDK3, resulting in 600 nM
Structure. 2007 Aug;15(8):992-1004.
PDK1
50 nM
30 min
Determination of IC50 for AZD7545 on PDK1, resulting in 87 nM
Structure. 2007 Aug;15(8):992-1004.
MelJuso
10 μM
120 h
Inhibition of PDK1 leads to growth suppression of NRAS mutant cells
Mol Cancer. 2017 Jun 8;16(1):102.
IPC298
10 μM
120 h
Inhibition of PDK1 leads to growth suppression of NRAS mutant cells
Mol Cancer. 2017 Jun 8;16(1):102.
SK-MEL-2
>100 μM
96 h
AZD7545 did not significantly inhibit proliferation in SK-MEL-2 cells, IC50 >100 μM
Int J Mol Sci. 2022 Mar 29;23(7):3745.
SK-MEL-28
>100 μM
96 h
AZD7545 did not significantly inhibit proliferation in SK-MEL-28 cells, IC50 >100 μM
Int J Mol Sci. 2022 Mar 29;23(7):3745.
MeWo
89.3 ±5.0 μM
96 h
AZD7545 inhibited proliferation in MeWo cells with an IC50 of 89.3 ±5.0 μM
Int J Mol Sci. 2022 Mar 29;23(7):3745.
A375
35.0 ±4.1 μM
96 h
AZD7545 inhibited proliferation in A375 cells with an IC50 of 35.0 ±4.1 μM
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