SR-12813

Names

[ Name ]:
SR-12813

[Synonym ]:
Tetraethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate
SRL
HTMT dimaleate
1ilh
4-[2,2-bis(diethoxyphosphoryl)ethenyl]-2,6-ditert-butylphenol
BIDD:PXR0009
SR 12813

Biological Activity

[Description]:

SR12813 is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, with an IC50 value of 0.85 μM.

[Related Catalog]:

Signaling Pathways >> Metabolic Enzyme/Protease >> HMG-CoA Reductase (HMGCR)

Research Areas >> Metabolic Disease

[Target]

IC50: 0.85 μM (HMG-CoA Reductase)

[In Vitro]

SR-12813 inhibits incorporation of tritiated water into cholesterol with an IC50 of 1.2 μM but has no effect on fatty acid synthesis. Furthermore, SR-12813 reduces cellular 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity with an IC50 of 0.85 μM[1]. Both 25-HC and SR-12813 can kill mammalian cells through blocking the synthesis of cholesterol, thereby they are ideal regents for lethal selection. SR-12813 kills HeLa cells at concentration range from 8 µM to 16 µM. SR-12813 kills wild type cells and mutant cells infected by Ad-Cre (SL-5+Cre), but the mutant SL-5 survives this condition. SR-12813 or 25-HC promotes the degradation of the 95-KDa full-length HMG-CoA reductase in wild type HeLa and SL-5 mutant cells[1].

[Kinase Assay]

Briefly, compounds are added to the cells in Me2SO (final concentration, 0.1%). After the experiment cells are lysed by the addition of 0.1 mL of 0.25% Brij 96, 0.1 M sucrose, 0.1 M KF, 50 mM KCl, 40 mM potassium dihydrophosphate, 30 mM EDTA, 5 mM dithiothreitol, pH 7.4 at room temperature. In some experiments KF is omitted to measure “total” HMG-CoA reductase activity. HMG-CoA reductase activity in the cell lysate is further determined.

[References]

[1]. Berkhout T, et al. The novel cholesterol-lowering drug SR-12813 inhibits cholesterol synthesis via an increased degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem. 1996 Jun 14;271(24):14376-82.

[2]. Jiang W, et al. Forward genetic screening for regulators involved in cholesterol synthesis using validation-based insertional mutagenesis. PLoS One. 2014 Nov 26;9(11):e112632.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.117g/cm3

[ Boiling Point ]:
552.6ºC at 760mmHg

[ Molecular Formula ]:
C₂₄H₄₂O₇P₂

[ Molecular Weight ]:
504.53400

[ Flash Point ]:
288ºC

[ Exact Mass ]:
504.24100

[ PSA ]:
110.91000

[ LogP ]:
7.81780

[ Vapour Pressure ]:
8.02E-13mmHg at 25°C

[ Index of Refraction ]:
1.504

[ Storage condition ]:
-20℃

Safety Information

[ Personal Protective Equipment ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

[ RIDADR ]:
NONH for all modes of transport

Articles

Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor.

Drug Metab. Dispos. 35 , 1495-501, (2007)

Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesi...

Cyclin-dependent kinase 2 negatively regulates human pregnane X receptor-mediated CYP3A4 gene expression in HepG2 liver carcinoma cells.

J. Biol. Chem. 283 , 30650-7, (2008)

The human pregnane X receptor (hPXR) regulates the expression of critical drug metabolism enzymes. One of such enzymes, cytochrome P450 3A4 (CYP3A4), plays critical roles in drug metabolism in hepatoc...

Isolation of mutant cells lacking Insig-1 through selection with SR-12813, an agent that stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

J. Biol. Chem. 279 , 43136-47, (2004)

Insig-1 and Insig-2 are membrane proteins of the endoplasmic reticulum that regulate lipid metabolism by the following two actions: 1) sterol-induced binding to 3-hydroxy-3-methylglutaryl-coenzyme A r...