In eukaryotic cells AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance. AMPK responds to changes in intracellular adenine nucleotide levels, being activated by an increase in AMP/ADP relative to ATP. Activation of AMPK increases the rate of catabolic (ATP-generating) pathways and decreases the rate of anabolic (ATP-utilising) pathways[1]. PF-06409577 is a potent and selective allosteric activator of AMPK α1β1γ1 isoform with an EC50 of 7 nM[2]. In broad panel screening against other receptors, channels, PDEs and kinases, PF-06409577 exhibits minimal off-target pharmacology. PF-06409577 demonstrates moderate plasma clearance in rats, dogs, and monkeys, and is well distributed with steady state distribution volume. Following oral administration of crystalline PF-06409577 in 0.5% methylcellulose suspension, PF-06409577 is rapidly absorbed in rats, dogs, and monkeys. The corresponding oral bioavailability values in rats, dogs, and monkeys, are 15%, 100%, and 59%, respectively. Oral administration of PF-06409577 (10, 30, and 100 mg/kg QD) results in dose-dependent reductions in proteinuria in the obese ZSF1 animals, with greater than 2-fold reduction in 24-hour urinary albumin loss compared to vehicle control after 60 days of treatment[2].
PF-06409577 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human primary hepatocytes
255 nM (EC50)
1 hour
To evaluate the effect of PF-06409577 on ACC phosphorylation, results showed that PF-06409577 dose-dependently increased phosphorylation of ACC at serine 79
EBioMedicine. 2018 May;31:122-132
Monkey primary hepatocytes
875 nM (EC50)
1 hour
To evaluate the effect of PF-06409577 on ACC phosphorylation, results showed that PF-06409577 dose-dependently increased phosphorylation of ACC at serine 79
EBioMedicine. 2018 May;31:122-132
Rat primary hepatocytes
69 nM (EC50)
1 hour
To evaluate the effect of PF-06409577 on ACC phosphorylation, results showed that PF-06409577 dose-dependently increased phosphorylation of ACC at serine 79
EBioMedicine. 2018 May;31:122-132
EndoC-βH3 cells
10 or 20 µM
1 hour
Significantly stimulated insulin secretion at high glucose concentrations
Diabetologia. 2022 Jun;65(6):997-1011
Mouse islets
25 µM
1.5 hours
Significantly stimulated insulin secretion at high glucose concentrations
To evaluate the inhibitory effect of PF-06409577 on WNV replication, results showed significant reduction in virus yield.
Antimicrob Agents Chemother. 2018 Jun 26;62(7):e00360-18
Vero cells
50 μg/ml
24 hours
To evaluate the effect of PF-06409577 on phosphorylation of AMPK and ACC, results showed significant increase in phosphorylation levels of AMPK and ACC.
Antimicrob Agents Chemother. 2018 Jun 26;62(7):e00360-18
MG-63 cells
1 µM
48/72 hours
Significantly inhibited cell viability and BrdU incorporation
Front Oncol. 2021 Jul 14;11:659181
U2OS cells
0.3-3 µM
48 hours
Inhibited cell viability and proliferation, induced cell apoptosis and cell cycle arrest
Front Oncol. 2021 Jul 14;11:659181
Primary human OS cells (Pri_OS-1/-2)
1 µM
48/72 hours
Significantly inhibited cell viability and BrdU incorporation
Front Oncol. 2021 Jul 14;11:659181
SaOs-2 cells
1 µM
48/72 hours
Significantly inhibited cell viability and BrdU incorporation
Front Oncol. 2021 Jul 14;11:659181
Peritoneal macrophages
10 µM
90 minutes
Treatment with PF-06409577 increased AMPK activity, as indicated by increased phosphorylation of ACC.
iScience. 2023 Oct 20;26(11):108269
Bone marrow-derived macrophages (BMDMs)
1 µM, 3 µM, 10 µM
90 minutes
PF-06409577 dose-dependently activated AMPK as indicated by increased phosphorylation of downstream substrates ULK1 and acetyl-CoA carboxylase (ACC), which are important for autophagy and fatty acid oxidation/de novo lipogenesis, respectively.
iScience. 2023 Oct 20;26(11):108269
Embryonic kidney cells
1, 3 or 10 µM
From culture day 0 to day 8
To evaluate the inhibitory effect of PF-06409577 on embryonic kidney cyst development. Results showed that PF-06409577 significantly reduced cyst number and size, with >30% inhibition at 10 μM.
FEBS Open Bio. 2022 Oct;12(10):1761-1770
MDCK cells
1, 3 or 10 µM
From day 5 to day 12
To evaluate the inhibitory effect of PF-06409577 on MDCK cyst growth. Results showed that PF-06409577 significantly inhibited cyst enlargement, with >40% inhibition at 10 μM.
FEBS Open Bio. 2022 Oct;12(10):1761-1770
PF-06409577 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Pkd1flox/flox;Ksp-Cre ADPKD mouse model
Subcutaneous injection
1 or 10 mg/kg/day
Once daily from postnatal day 6 to day 12
To evaluate the inhibitory effect of PF-06409577 on renal cyst development in ADPKD mice. Results showed that PF-06409577 significantly reduced kidney size and cyst area, with >35% inhibition at 10 mg/kg.
FEBS Open Bio. 2022 Oct;12(10):1761-1770
CB.17 severe combined immunodeficient (SCID) mice
U2OS cells and primary human OS cells (Pri_OS-1) xenograft model
Oral
10/30 mg/kg
Daily for 24 days
Significantly inhibited the growth of U2OS and primary OS cell xenografts
Front Oncol. 2021 Jul 14;11:659181
Mice
High fat diet-induced metabolic syndrome model
Oral
100 mg/kg
Once daily for 42 days
To evaluate the effect of PF-06409577 on hepatic lipids and cholesterol, results showed that PF-06409577 significantly reduced hepatic triacylglycerol (TAG) and cholesterol levels, and decreased mRNA expression of markers of hepatic fibrosis
EBioMedicine. 2018 May;31:122-132
Mice
ApoE-/- mice and PCSK9 over-expression mouse models
Oral gavage
100 mg/kg
Once daily for 6 weeks
PF-06409577 reduced atherosclerosis in two mouse models in a myeloid-derived AMPK b1 dependent manner, suggesting a critical role for macrophages.
搜索
