PF429242 2HCl is a reversible and competitive SREBP site 1 protease (S1P) inhibitor with IC50 value of 175nM.
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PF429242 dihydrochloride is a reversible and competitive inhibitor of SREBP site 1 protease (S1P) with an IC50 of 175 nM[1].
体内研究
In mice treated with PF-429242 for 24 hours, there is a suppression of hepatic SREBP target gene expression, and the rates of cholesterol and fatty acid synthesis in the liver are reduced[1].
体外研究
PF-429242 at 10 μM inhibits endogenous SREBP processing in Chinese hamster ovary cells. It also reduces signaling from an SRE-luciferase reporter gene in human embryonic kidney 293 cells and decreases the expression of endogenous SREBP target genes in HepG2 cells. Additionally, in HepG2 cells, PF-429242 inhibits cholesterol synthesis with an IC50 of 0.5 μM[1].
The addition of PF-429242 at 30 μM significantly suppresses infectious viral titers and viral RNA copies in cell culture fluids. Treatment with PF-429242 also reduces DENV2 yields in the cultured fluids of human-derived HEK-293 and Hep G2 cells, as well as non-human-primate derived LLC-MK2 cells[2].
PF-429242 effectively inhibits the processing of GPC from the prototypic arenaviruses lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV). This inhibition correlates with the compound’s potent antiviral activity against LCMV and LASV in cultured cells[3].
PF-429242 inhibited AVP-induced increase in V2R expression and reduced medium sPRR content
JCI Insight. 2019 Apr 4;4(7):e124174
Huh-7.5.1 cells
10 µM
24 hours
Inhibition of SKI-1/S1P activity, blocking nuclear accumulation of SREBP-1
PLoS Pathog. 2012 Jan;8(1):e1002468
Mouse cortical collecting duct cell line (mpkCCD)
10 µM
24 hours
To investigate the effect of S1P inhibition on Ang II-induced ENaC activity, results showed that PF-429242 blocked Ang II-induced ENaC activity, and this effect was reversed by sPRR-His supplementation.
Hypertension. 2021 Feb;77(2):405-416
Differentiated 3T3 cells
10 µM
24 hours
To investigate the effect of PF429242 on insulin signaling, results showed that PF429242 inhibited endogenous sPRR production, leading to reduced glucose uptake, which was partially restored by sPRR-His supplementation.
JCI Insight. 2020 Apr 9;5(7):e128061
U87 cells
10 µM
24 hours
To verify the inhibitory effect of PF-429242 on SREBP activity, results showed that PF-429242 could inhibit the expression of SREBP target genes
J Biol Chem. 2016 Aug 12;291(33):17001-8
HeLa cells
10 µM
24 hours
To verify the inhibitory effect of PF-429242 on SREBP activity, results showed that PF-429242 could inhibit the expression of SREBP target genes
J Biol Chem. 2016 Aug 12;291(33):17001-8
Oligodendrocyte precursor cells (OPCs)
1-3 µM
3 days
Preventing SREBP processing inhibited process growth and reduced the expression level of myelin basic protein (MBP)
J Neurochem. 2017 Jan;140(1):53-67
293T cells
1, 10, 30 µM
36 hours
To evaluate the inhibitory effect of PF-429242 on LCMV and LASV GPC cleavage. Results showed that PF-429242 effectively inhibited the cleavage of LCMV and LASV GPC but had no effect on GPCf.
J Virol. 2011 Jan;85(2):795-803
BHK-21 baby hamster kidney fibroblast cells
20 µM
48 hours
To test the inhibitory effect of PF-429242 on LCMV viral replication
ACS Biomater Sci Eng. 2015 Nov 9;1(11):1050-1054
BHK-21 cells
0, 1, 10, 30 µM
48 hours
To evaluate the inhibitory effect of PF-429242 on LCMV replication. Results showed that PF-429242 significantly inhibited LCMV replication but had a weaker effect on rLCMV-GPCf.
J Virol. 2011 Jan;85(2):795-803
PLC5 cells
10 µM
6 hours
Inhibition of S1P enhanced the anticancer activity of GSK343
Am J Cancer Res. 2019 Oct 1;9(10):2120-2139
HepG2 cells
10 µM
6 hours
Inhibition of S1P enhanced the anticancer activity of GSK343
Am J Cancer Res. 2019 Oct 1;9(10):2120-2139
MEFs cells
10 µM
60 hours
To verify the effect of PF-429242 on cell viability, results showed that PF-429242 had a minor effect on cell viability
J Biol Chem. 2016 Aug 12;291(33):17001-8
RPE cells
10 µM
60 hours
To verify the effect of PF-429242 on cell viability, results showed that PF-429242 had a minor effect on cell viability
J Biol Chem. 2016 Aug 12;291(33):17001-8
U2OS cells
10 µM
60 hours
To verify the effect of PF-429242 on cell viability, results showed that PF-429242 had a minor effect on cell viability
J Biol Chem. 2016 Aug 12;291(33):17001-8
SH-SY5Y cells
10 µM
60 hours
To verify the effect of PF-429242 on cell viability, results showed that PF-429242 had a minor effect on cell viability
J Biol Chem. 2016 Aug 12;291(33):17001-8
Mouse peritoneal macrophages
200, 100, 50, 25, 12.5, and 6.25 µM
72 hours
To evaluate the toxicity of PF-429242 against mammalian cells. Results showed that PF-429242 had low toxicity against macrophages with a CC50 value of 189.07 μM.
Front Microbiol. 2021 Jan 28;12:583834
Leishmania infantum promastigotes
100, 50, 10, 5, 1, 0.5, 0.1, and 0.01 µM
72 hours
To evaluate the antileishmanial effect of PF-429242 against L. infantum promastigotes. Results showed that PF-429242 had good activity against promastigotes with an IC50 value of 2.78 μM.
Front Microbiol. 2021 Jan 28;12:583834
Leishmania amazonensis promastigotes
0–128 µM
72 hours
To evaluate the leishmanicidal activity of PF-429242 against wild-type and simvastatin-resistant strains. Results showed that the EC50 for PF-429242 was 21.50 μM in LaSimR compared to 10.17 μM in wild-type, indicating cross-resistance in the resistant strain.
Microorganisms. 2022 Feb 9;10(2):398
PF429242 2HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NPG mice
HepG2 tumor xenograft model
Intravenous injection
20 mg/kg
Twice weekly for 4 weeks
PF-429242 inhibited HepG2 tumor growth in vivo
Am J Cancer Res. 2023 Sep 15;13(9):4125-4144
C57/BL6 mice
Wild-type mice
Subcutaneous injection
20 mg/kg/day
For 4 days
PF-429242 treatment caused polyuria and hypoosmotic urine in mice and reduced renal V2R and AQP2 expression
JCI Insight. 2019 Apr 4;4(7):e124174
B6129SF1/J mice
Ang II-induced hypertension model
Subcutaneous implantation via minipump
20 mg/kg/day
Continuous for 6 days
To evaluate the effect of PF-429242 on Ang II-induced hypertension, results showed that S1P inhibition significantly attenuated Ang II-induced hypertension, accompanied by suppressed urinary and renal medullary renin levels and reduced expression of renal medullary α-ENaC.
Hypertension. 2021 Feb;77(2):405-416
C57/BL6 mice
Diet-induced obesity model
Subcutaneous injection
20 mg/kg/day
Once daily for 2 weeks
To investigate the effect of PF429242 on glucose metabolism, results showed that PF429242 significantly increased blood glucose and insulin levels and worsened glucose tolerance and insulin tolerance, which were corrected by sPRR-His supplementation.
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