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squalene synthase

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Target id: 645

Nomenclature: squalene synthase

Family: Lanosterol biosynthesis pathway

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 2 417 8p23.1 FDFT1 farnesyl-diphosphate farnesyltransferase 1 30
Mouse 2 416 14 33.24 cM Fdft1 farnesyl diphosphate farnesyl transferase 1
Rat 2 416 15p12 Fdft1 farnesyl diphosphate farnesyl transferase 1
Previous and Unofficial Names Click here for help
farnesyltransferase | FDFT1 | presqualene synthase | presqualene-diphosphate synthase | SQS | squalene synthetase | SSase | FPP:FPP farnesyltransferase
Database Links Click here for help
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ChEMBL Target
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KEGG Gene
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RefSeq Nucleotide
RefSeq Protein
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Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human squalene synthase
PDB Id:  3VJ8
Resolution:  1.52Å
Species:  Human
References:  21
Image of receptor 3D structure from RCSB PDB
Description:  Human squalene synthase in complex with 2-(1-{2-[(4R,6S)-8-chloro-6-(2,3-dimethoxyphenyl)-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl]acetyl}-4-piperidinyl)acetic acid
PDB Id:  3V66
Ligand:  compound 15a [PMID: 22464687]
Resolution:  1.8Å
Species:  Human
References:  14
Enzyme Reaction Click here for help
EC Number: 2.5.1.21 2trans,trans-farnesyl diphosphate -> presqualene diphosphate + diphosphate
presqualene diphosphate + NAD(P)H + H+ -> squalene + diphosphate + NAD(P)+
Substrates and Reaction Kinetics Click here for help
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
NADPH Substrate is endogenous in the given species Rn Km 4x10-5 M pKm 4.4 in vitro assay pH 7.4, 37ºC Concentration of substrates: 2.0mM NADPH, 10µM FPP, 5.0mM MgCl2 in a total volume of 100µl 35
trans,trans-farnesyl diphosphate Substrate is endogenous in the given species Rn Km 1x10-6 M pKm 6.0 in vitro assay pH 7.4, 37ºC Concentration of substrates: 2.0mM NADPH, 10µM FPP, 5.0mM MgCl2 in a total volume of 100µl 35
trans,trans-farnesyl diphosphate Substrate is endogenous in the given species Rn Km 1.8x10-6 M pKm 5.7 recombinant enzyme expressed in E coli, isolated, in vitro assay pH 7.5 Concentration of FPP: 0.4-10µM 40
trans,trans-farnesyl diphosphate Substrate is endogenous in the given species Hs Km 2.3x10-6 M pKm 5.6 recombinant enzyme expressed in E coli, isolated, in vitro assay pH 7.5 Concentration of FPP: 0.4-10µM 40
NADH Substrate is endogenous in the given species Rn Km 8x10-4 M pKm 3.1 in vitro assay pH 7.4, 37ºC Concentration of substrates: 2.0mM NADPH, 10µM FPP, 5.0mM MgCl2 in a total volume of 100µl 35
trans,trans-farnesyl diphosphate Substrate is endogenous in the given species Rn Vmax 1.2 µmol/min/mg in vitro assay pH 7.4, 37ºC Concentration of substrates: 2.0mM NADPH, 10µM FPP, 5.0mM MgCl2 in a total volume of 100µl 35
Cofactors Click here for help
Cofactor Species Comments Reference
Mg2+ Human 32
NADPH Human 32
NADH Human 32

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
zaragozic acid B Small molecule or natural product Rn Inhibition 10.5 pKi 1
pKi 10.5 (Ki 2.9x10-11 M) [1]
Conditions: Concentration of substrates: 0.2-10µM FPP, 10mM NADPH. pH 7.5, 30°C
zaragozic acid C Small molecule or natural product Rn Inhibition 10.4 pKi 1,10
pKi 10.4 (Ki 4.5x10-11 M) [1,10]
Description: Inhibition of rat squalene synthase
Conditions: Concentration of substrates: 0.2-10µM FPP, 10mM NADPH. pH 7.5, 30°C (8419946)
zaragozic acid A Small molecule or natural product Ligand has a PDB structure Rn Inhibition 10.1 pKi 1
pKi 10.1 (Ki 7.8x10-11 M) [1]
Description: Compound was tested for inhibition of squalene synthase in rat liver.
Conditions: Concentration of substrates: 0.2-10µM FPP, 10mM NADPH. pH 7.5, 30°C
zaragozic acid A Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.6 pKi 37
pKi 9.6 (Ki 2.5x10-10 M) [37]
Description: Human enzyme expressed in yeast, in vitro assay
Conditions: pH 7.4, 37°C
compound 1e [Brown et al., 1997] Small molecule or natural product Rn Inhibition 8.7 pKi 7
pKi 8.7 (Ki 2x10-9 M) [7]
Description: Tested for its inhibitory activity against rat microsomal quinuclidine squalene synthase (SQS)
compound 6 [Biller et al., 1991] Small molecule or natural product Rn Inhibition 7.4 pKi 3
pKi 7.4 (Ki 3.7x10-8 M) [3]
Description: Tested for inhibitory potency against rat liver microsomal squalene synthase
compound 1c [Brown et al., 1997] Small molecule or natural product Hs Inhibition 7.4 pKi 7
pKi 7.4 (Ki 4.3x10-8 M) [7]
Description: Tested for its inhibitory activity against human microsomal quinuclidine squalene synthase (SQS)
compound 15 [PMID: 19456099] Small molecule or natural product Hs Inhibition 6.5 pKi 39
pKi 6.5 (Ki 3x10-7 M) [39]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli cells assessed as conversion of [3H]FPP to squalene by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
BPH-830 Small molecule or natural product Hs Inhibition 6.3 pKi 39
pKi 6.3 (Ki 5.3x10-7 M) [39]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli cells assessed as conversion of [3H]FPP to squalene by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
compound 13 [PMID: 19456099] Small molecule or natural product Hs Inhibition 6.3 pKi 39
pKi 6.3 (Ki 5.2x10-7 M) [39]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli cells assessed as conversion of [3H]FPP to squalene by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
SQ-109 Small molecule or natural product Guide to Malaria Pharmacology Ligand Hs Inhibition 6.1 pKi 20
pKi 6.1 (Ki 7.4x10-7 M) [20]
compound 21 [PMID: 7473541] Small molecule or natural product Ligand has a PDB structure Rn Inhibition 11.4 pIC50 5
pIC50 11.4 [5]
Description: Inhibition of rat microsomal squalene synthase
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 5d [PMID: 7966163] Small molecule or natural product Rn Inhibition 10.4 pIC50 27
pIC50 10.4 (IC50 4x10-11 M) [27]
Description: Tested for inhibition against squalene synthase enzyme in rat liver
Conditions: Substrate concentration: 5µM FPP
compound 5d [PMID: 7966163] Small molecule or natural product Rn Inhibition 10.4 pIC50 27
pIC50 10.4 (IC50 4x10-11 M) [27]
Description: Tested for inhibition against squalene synthase enzyme in rat liver
Conditions: Substrate concentration: 5µM FPP
compound 19 [PMID: 7473541] Small molecule or natural product Rn Inhibition 10.3 pIC50 5
pIC50 10.3 (IC50 5x10-11 M) [5]
Description: Inhibition of rat microsomal squalene synthase
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 6g [PMID: 7966163] Small molecule or natural product Rn Inhibition 10.2 pIC50 27
pIC50 10.2 (IC50 6x10-11 M) [27]
Description: Tested for inhibition against squalene synthase enzyme in rat liver
Conditions: Substrate concentration: 5µM FPP
compound 4e [PMID: 7966163] Small molecule or natural product Rn Inhibition 10.1 pIC50 27
pIC50 10.1 (IC50 7x10-11 M) [27]
Description: Tested for inhibition against squalene synthase enzyme in rat liver
Conditions: Substrate concentration: 5µM FPP
compound 6d [PMID: 7966163] Small molecule or natural product Rn Inhibition 10.1 pIC50 27
pIC50 10.1 (IC50 9x10-11 M) [27]
Description: Tested for inhibition against squalene synthase enzyme in rat liver
Conditions: Substrate concentration: 5µM FPP
compound 6c [PMID: 7966163] Small molecule or natural product Rn Inhibition 9.9 pIC50 27
pIC50 9.9 (IC50 1.2x10-10 M) [27]
Description: Tested for inhibition against squalene synthase enzyme in rat liver
Conditions: Substrate concentration: 5µM FPP
compound 3f [PMID: 7966163] Small molecule or natural product Rn Inhibition 9.9 pIC50 27
pIC50 9.9 (IC50 1.3x10-10 M) [27]
Description: Tested for inhibition against squalene synthase enzyme in rat liver
Conditions: Substrate concentration: 5µM FPP
L-735021 Small molecule or natural product Rn Inhibition 9.9 pIC50 27
pIC50 9.9 (IC50 1.4x10-10 M) [27]
Description: Tested for inhibition against squalene synthase enzyme in rat liver
Conditions: Substrate concentration: 5µM FPP
compound 28 [PMID: 7473541] Small molecule or natural product Rn Inhibition 9.7 pIC50 5
pIC50 9.7 (IC50 2x10-10 M) [5]
Description: Inhibition of rat microsomal squalene synthase
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 20 [PMID: 7473541] Small molecule or natural product Rn Inhibition 9.2 pIC50 5
pIC50 9.2 (IC50 6x10-10 M) [5]
Description: Inhibition of rat microsomal squalene synthase
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
J-104118 Small molecule or natural product Hs Inhibition 9.1 – 9.3 pIC50 16
pIC50 9.3 (IC50 5.2x10-10 M) [16]
Description: Inhibitory activity against HepG2 Squalene Synthase (SQS)
pIC50 9.1 (IC50 7.3x10-10 M) [16]
Description: Inhibitory activity against HepG2 Squalene Synthase (SQS)
zaragozic acid A Small molecule or natural product Ligand has a PDB structure Hs Inhibition 9.1 pIC50 40
pIC50 9.1 (7x10-10 M) [40]
Description: in vitro, soluable microsomal enzymes purified from rat and human liver microsomes
Conditions: Concentration of FPP: 20µM
compound 6 [PMID: 7629799] Small molecule or natural product Rn Inhibition 9.1 pIC50 23-24
pIC50 9.1 (IC50 7x10-10 M) [24]
Description: Inhibition rat liver microsomal squalene synthase. In vivo assay
pIC50 9.1 (IC50 7x10-10 M) [23]
Description: Inhibitory activity against rat liver microsomal squalene synthase was determined using [3H]-FPP as radioligand
compound 6 [PMID: 7629799] Small molecule or natural product Hs Inhibition 9.0 pIC50 38
pIC50 9.0 (IC50 1x10-9 M) [38]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21 (DE3) cells assessed as formation of 1,10-dioic acid metabolite by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
SQ-34919 Small molecule or natural product Rn Inhibition 9.0 pIC50 23-24
pIC50 9.0 (IC50 1x10-9 M) [24]
Description: Inhibition rat liver microsomal squalene synthase
pIC50 9.0 (IC50 1x10-9 M) [23]
Description: Inhibitory activity against rat liver microsomal squalene synthase was determined using [3H]-FPP as radioligand
Conditions: compound is a tetrasodium salt
compound 15a [PMID: 22464687] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.9 pIC50 14
pIC50 8.9 (IC50 1.3x10-9 M) [14]
E5700 Small molecule or natural product Hs Inhibition 8.8 pIC50 31
pIC50 8.8 (IC50 1.5x10-9 M) [31]
Description: Inhibition of human recombinant squalene synthase
Conditions: Substrate concentration: 0.5µM FPP. pH 7.4, 37°C
compound 32 [PMID: 19191557] Small molecule or natural product Hs Inhibition 8.7 pIC50 38
pIC50 8.7 (IC50 2x10-9 M) [38]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21 (DE3) cells assessed as formation of 1,10-dioic acid metabolite by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
compound 2e [PMID: 7629799] Small molecule or natural product Rn Inhibition 8.6 pIC50 24
pIC50 8.6 (IC50 2.5x10-9 M) [24]
Description: Inhibition rat liver microsomal squalene synthase
J-104123 Small molecule or natural product Hs Inhibition 8.6 pIC50 17
pIC50 8.6 (IC50 2.5x10-9 M) [17]
Description: Inhibitory activity against squalene synthase (SQS) obtained from HepG2 cells
compound 2d [PMID: 7629799] Small molecule or natural product Rn Inhibition 8.6 pIC50 24
pIC50 8.6 (IC50 2.6x10-9 M) [24]
Description: Inhibition rat liver microsomal squalene synthase
compound 23 [PMID: 8709131] Small molecule or natural product Rn Inhibition 8.5 pIC50 6
pIC50 8.5 (IC50 3x10-9 M) [6]
Description: In vitro inhibition against rat microsomal squalene synthase (SS)
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 3 [PMID: 19191557] Small molecule or natural product Hs Inhibition 8.5 pIC50 38
pIC50 8.5 (IC50 3x10-9 M) [38]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21 (DE3) cells assessed as formation of 1,10-dioic acid metabolite by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
compound 8 [PMID: 19191557] Small molecule or natural product Hs Inhibition 8.5 pIC50 38
pIC50 8.5 (IC50 3x10-9 M) [38]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21 (DE3) cells assessed as formation of 1,10-dioic acid metabolite by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
compound 15 [PMID: 8709131] Small molecule or natural product Rn Inhibition 8.4 pIC50 6
pIC50 8.4 (IC50 4x10-9 M) [6]
Description: In vitro inhibition against rat microsomal squalene synthase (SS)
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 7 [PMID: 8496919] Small molecule or natural product Rn Inhibition 8.4 pIC50 29
pIC50 8.4 (IC50 4x10-9 M) [29]
Description: Tested for inhibitory activity against squalene synthetase in the presence of inorganic pyrophosphate (PPi)
Conditions: Concentration of substrate: 10mM FPP. pH 7.4, 37°C
compound 35 [PMID: 19191557] Small molecule or natural product Hs Inhibition 8.4 pIC50 38
pIC50 8.4 (IC50 4x10-9 M) [38]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21 (DE3) cells assessed as formation of 1,10-dioic acid metabolite by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
compound 17 [PMID: 8709131] Small molecule or natural product Rn Inhibition 8.3 pIC50 6
pIC50 8.3 (IC50 5x10-9 M) [6]
Description: In vitro inhibition against rat microsomal squalene synthase (SS)
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 21 [PMID: 19191557] Small molecule or natural product Hs Inhibition 8.3 pIC50 38
pIC50 8.3 (IC50 5x10-9 M) [38]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21 (DE3) cells assessed as formation of 1,10-dioic acid metabolite by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
compound 2a (+) [PMID: 8709131] Small molecule or natural product Rn Inhibition 8.1 pIC50 6
pIC50 8.1 (IC50 7x10-9 M) [6]
Description: In vitro inhibition against rat microsomal squalene synthase (SS)
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 8 [Brinkman et al., 1996] Small molecule or natural product Rn Inhibition 8.1 pIC50 4
pIC50 8.1 (IC50 9x10-9 M) [4]
Description: Compound was tested for inhibitory activity against squalene synthase using rat liver microsomal assay
Conditions: Substrate concentration: 10µM FPP. pH 7.4, 37°C
compound 7 [Brinkman et al., 1996] Small molecule or natural product Rn Inhibition 8.1 pIC50 4
pIC50 8.1 (IC50 9x10-9 M) [4]
Description: Compound was tested for inhibitory activity against squalene synthase using rat liver microsomal assay
Conditions: Substrate concentration: 10µM FPP. pH 7.4, 37°C
compound 4 [Brinkman et al., 1996] Small molecule or natural product Rn Inhibition 8.0 pIC50 4
pIC50 8.0 (IC50 1x10-8 M) [4]
Description: Compound was tested for inhibitory activity against squalene synthase using rat liver microsomal assay
Conditions: Substrate concentration: 10µM FPP. pH 7.4, 37°C
compound 4 [PMID: 8709131] Small molecule or natural product Rn Inhibition 8.0 pIC50 6
pIC50 8.0 (IC50 1.1x10-8 M) [6]
Description: In vitro inhibition against rat microsomal squalene synthase (SS)
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 16a [Sharratt et al., 1994] Small molecule or natural product Rn Inhibition 8.0 pIC50 33
pIC50 8.0 (IC50 1.1x10-8 M) [33]
Description: In vitro inhibitory concentration against squalene synthase from male rat liver microsomes
compound 5j [PMID: 9216829] Small molecule or natural product Rn Inhibition 7.9 pIC50 11
pIC50 7.9 (IC50 1.3x10-8 M) [11]
Description: In vitro inhibitory activity against Squalene Synthase. Enzyme from rat liver microsomes.
compound 5m [PMID: 9216829] Small molecule or natural product Rn Inhibition 7.8 pIC50 11
pIC50 7.8 (IC50 1.4x10-8 M) [11]
Description: In vitro inhibitory activity against Squalene Synthase
compound 3a [PMID: 12238936] Small molecule or natural product Hs Inhibition 7.8 pIC50 25
pIC50 7.8 (IC50 1.5x10-8 M) [25]
Description: Inhibition of squalene synthase from human hepatoma cells (HepG2). *this value also obtained for rat liver enzyme for this compound
Conditions: Substrate concentrations: 5µM FPP, 1mM NADPH. pH 7.4, 37°C
compound 3f [PMID: 12238936] Small molecule or natural product Hs Inhibition 7.8 pIC50 25
pIC50 7.8 (IC50 1.5x10-8 M) [25]
Description: Inhibition of squalene synthase from human hepatoma cells (HepG2)
Conditions: Substrate concentrations: 5µM FPP, 1mM NADPH. pH 7.4, 37°C
compound 4 [PMID: 8576905] Small molecule or natural product Rn Inhibition 7.8 pIC50 23
pIC50 7.8 (IC50 1.5x10-8 M) [23]
Description: Inhibitory activity against rat liver microsomal squalene synthase was determined using [3H]-FPP as radioligand
compound 1 [Overhand et al., 1997] Small molecule or natural product Hs Inhibition 7.7 pIC50 26
pIC50 7.7 (IC50 1.8x10-8 M) [26]
Description: Inhibition of Squalene Synthase
NB-598 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.7 pIC50 12
pIC50 7.7 (IC50 2x10-8 M) [12]
Description: In vitro ability to inhibit cholesterol biosynthesis in HepG2 cells in culture from [14C]-acetate
Conditions: IC50 calculated from % cholesterol inhibition
1-allyl-2-[3-(isopropylamino)propoxy]-9H-carbazole Small molecule or natural product Hs Inhibition 7.5 pIC50 15
pIC50 7.5 (IC50 3.2x10-8 M) [15]
Description: in vitro. Rat and human liver microsomes assayed using the Amin technique.
Conditions: Substrate concentrations: 5µM FPP, 1mM NADPH. pH 7.5, 30°C. IC50 values determined by a single experimental run in duplicate.
compound 4q [PMID: 7650673] Small molecule or natural product Hs Inhibition 7.2 pIC50 12
pIC50 7.2 (IC50 6x10-8 M) [12]
Description: In vitro ability to inhibit cholesterol biosynthesis in HepG2 cells in culture from [14C]-mevalonate.
Conditions: IC50 calculated from % cholesterol inhibition
YM-75440 Small molecule or natural product Hs Inhibition 7.2 pIC50 15
pIC50 7.2 (6.3x10-8 M) [15]
Description: in vitro . Rat and human liver microsomes assayed using the Amin techinique
Conditions: Substrate concentrations: 5µM FPP, 1mM NADPH. pH 7.5, 30°C. IC50 values determined by a single experimental run in duplicate
1-allyl-2-[3-(isopropylamino)propoxy]-9H-carbazole Small molecule or natural product Rn Inhibition 7.2 pIC50 15
pIC50 7.2 (IC50 6.6x10-8 M) [15]
Description: in vitro. Rat and human liver microsomes assayed using the Amin technique.
Conditions: Substrate concentrations: 5µM FPP, 1mM NADPH. pH 7.5, 30°C. IC50 values determined by a single experimental run in duplicate.
1-allyl-2-[3-(isopropylamino)propoxy]-9H-xanthen-9-one Small molecule or natural product Hs Inhibition 6.9 pIC50 15
pIC50 6.9 (IC50 1.2x10-7 M) [15]
Description: in vitro. Rat and human liver microsomes assayed using the Amin technique.
Conditions: Substrate concentrations: 5µM FPP, 1mM NADPH. pH 7.5, 30°C. IC50 values determined by a single experimental run in duplicate.
1-allyl-2-[3-(isopropylamino)propoxy]-9H-xanthen-9-one Small molecule or natural product Rn Inhibition 6.9 pIC50 15
pIC50 6.9 (IC50 1.2x10-7 M) [15]
Description: in vitro. Rat and human liver microsomes assayed using the Amin technique.
Conditions: Substrate concentrations: 5µM FPP, 1mM NADPH. pH 7.5, 30°C, IC50 values determined by a single experimental run in duplicate.
compound 15 [Biller et al., 1993] Small molecule or natural product Rn Inhibition 6.9 pIC50 2
pIC50 6.9 (IC50 1.25x10-7 M) [2]
Description: Tested for inhibitory potency against rat liver microsomal squalene synthase
CP-294838 Small molecule or natural product Rn Inhibition 6.9 pIC50 40
pIC50 6.9 (1.3x10-7 M) [40]
Description: in vitro, soluable microsomal enzymes purified from rat and human liver microsomes
Conditions: Concentration of FPP: 20µM
compound 12 [Wattanasin et al.,1997] Small molecule or natural product Rn Inhibition 6.6 – 6.8 pIC50 41
pIC50 6.8 (IC50 1.7x10-7 M) [41]
Description: The compound was tested for inhibition of purified rat hepatic squalene synthase in the presence of 1.2 mM NADPH and 1.0 mM inorganic pyrophosphate. In vitro assay.
pIC50 6.6 (IC50 2.3x10-7 M) [41]
Description: Inhibitory activity against squalene synthase using rat liver microsomal assay
compound 14 [PMID: 9871507] Small molecule or natural product Rn Inhibition 6.6 pIC50 36
pIC50 6.6 (IC50 2.4x10-7 M) [36]
Description: Compound was tested for inhibition of squalene synthase from rat liver microsomes using [3H]-Farnesyl pyrophosphate (FPP) as substrate
Conditions: pH 7.4
L-731120 Small molecule or natural product Rn Inhibition 6.6 pIC50 13
pIC50 6.6 (IC50 2.6x10-7 M) [13]
Description: In vitro inhibitory activity against rat squalene synthase
ibandronic acid Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Inhibition 6.2 pIC50 22
pIC50 6.2 (IC50 6.4x10-7 M) [22]
Description: Inhibition of squalene synthase in rat liver microsomes assessed as conversion of [1-3H]FPP to [3H]squalene level after 60 mins by liquid scintillation counting
Conditions: 0.02µCi FPP, 2mM NADPH. 30°C, assay performed in duplicate
compound 4g [PMID: 17709461] Small molecule or natural product Hs Inhibition 6.2 pIC50 8
pIC50 6.2 (IC50 6.6x10-7 M) [8]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21(DE3 pLysS) by liquid scintillation counter
Conditions: Substrate concentration: 0.5µM FPP, 0.25mM NADPH. pH 7.4, 37°C
L-731128 Small molecule or natural product Rn Inhibition 6.1 pIC50 13
pIC50 6.1 (IC50 7.67x10-7 M) [13]
Description: In vitro inhibitory activity against rat squalene synthase
compound 1 [PMID: 8496942] Small molecule or natural product Rn Inhibition 5.2 – 7.0 pIC50 28
pIC50 7.0 (IC50 1x10-7 M) [28]
Description: Inhibitory activity against squalene synthetase in the presence of inorganic pyrophosphate in rat liver microsomal assay
pIC50 5.2 (IC50 6.9x10-6 M) [28]
Description: Inhibitory activity against squalene synthetase in rat liver microsomal assay
compound 9 [PMID: 18754614] Small molecule or natural product Rn Inhibition 6.0 pIC50 19
pIC50 6.0 (IC50 1x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 11 [PMID: 7473541] Small molecule or natural product Rn Inhibition 5.8 pIC50 5
pIC50 5.8 (IC50 1.4x10-6 M) [5]
Description: Inhibition of rat microsomal squalene synthase
Conditions: Concentration of substrates: 20µM FPP, 0.9 mM NADPH. 37°C
compound 17 [Shechter et al., 1996] Small molecule or natural product Rn Inhibition 5.7 pIC50 34
pIC50 5.7 (IC50 2x10-6 M) [34]
Description: Inhibitory activity against rat hepatic squalene synthase
compound 8 [PMID: 18754614] Small molecule or natural product Rn Inhibition 5.7 pIC50 19
pIC50 5.7 (IC50 2x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 19 [PMID: 18754614] Small molecule or natural product Rn Inhibition 5.5 pIC50 19
pIC50 5.5 (IC50 3x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 14 [PMID: 19191557] Small molecule or natural product Hs Inhibition 5.4 pIC50 38
pIC50 5.4 (IC50 3.7x10-6 M) [38]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21 (DE3) cells assessed as formation of 1,10-dioic acid metabolite by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
compound 20 [PMID: 20299227] Small molecule or natural product Rn Inhibition 5.4 pIC50 22
pIC50 5.4 (IC50 3.71x10-6 M) [22]
Description: Inhibition of squalene synthase in rat liver microsomes assessed as conversion of [1-3H]FPP to [3H]squalene level after 60 mins by liquid scintillation counting
Conditions: 0.02µCi FPP, 2mM NADPH. 30°C, assay performed in duplicate
compound 18 [PMID: 18754614] Small molecule or natural product Rn Inhibition 5.4 pIC50 19
pIC50 5.4 (IC50 4x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 20 [Shechter et al., 1996] Small molecule or natural product Rn Inhibition 5.3 pIC50 34
pIC50 5.3 (IC50 5x10-6 M) [34]
Description: Inhibitory activity against rat hepatic squalene synthase
compound 10 [PMID: 18754614] Small molecule or natural product Rn Inhibition 5.3 pIC50 19
pIC50 5.3 (IC50 5x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 5 [PMID: 18754614] Small molecule or natural product Rn Inhibition 5.3 pIC50 19
pIC50 5.3 (IC50 5x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 17 [PMID: 18754614] Small molecule or natural product Rn Inhibition 5.2 pIC50 19
pIC50 5.2 (IC50 6x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 7 [PMID: 18754614] Small molecule or natural product Rn Inhibition 5.2 pIC50 19
pIC50 5.2 (IC50 7x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 4 [PMID: 18754614] Small molecule or natural product Rn Inhibition 5.2 pIC50 19
pIC50 5.2 (IC50 7x10-6 M) [19]
Description: Inhibition of squalene synthase in rat liver microsome measured by convertion of [3H]FPP to squalene
Conditions: Substrate concentrations: 0.5mM NADPH, 0.5µM FPP. pH 7.4, 37°C
compound 19 [PMID: 19191557] Small molecule or natural product Hs Inhibition 4.9 pIC50 38
pIC50 4.9 (IC50 1.17x10-5 M) [38]
Description: Inhibition of human recombinant squalene synthase expressed in Escherichia coli BL21 (DE3) cells assessed as formation of 1,10-dioic acid metabolite by liquid scintillation
Conditions: Substrate concentrations: 0.25mM NADPH, 0.1nmol FPP in a volume of 200µL. pH 7.4, 37°C
compound 12 [PMID: 20299227] Small molecule or natural product Rn Inhibition 4.8 pIC50 22
pIC50 4.8 (IC50 1.768x10-5 M) [22]
Description: Inhibition of squalene synthase in rat liver microsomes assessed as conversion of [1-3H]FPP to [3H]squalene level after 60 mins by liquid scintillation counting
Conditions: 0.02µCi FPP, 2mM NADPH. 30°C, assay performed in duplicate
View species-specific inhibitor tables

Some of the inhibitors above have been selected as representative structures from sets of stucturally similar compounds with bioactivity data at this target on ChEMBLdb.

Click here for a summary of the ChEMBL bioactivity data 


Tissue Distribution Click here for help
Liver
Species:  Human
Technique:  Northern blot
References:  18
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Recombinant chromosome 8 syndrome
OMIM: 179613
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Description:  Potassium residue at position 45 is substituted with arginine, resulting in increased total cholesterol and non-high density lipoprotein cholesterol.
References:  9

References

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1. Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD. (1993) Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc Natl Acad Sci USA, 90 (1): 80-4. [PMID:8419946]

2. Biller SA, Abt JW, Pudzianowski AT, Rich LC, Slusarchyk DA, Ciosek Jr CP. (1993) Aromatic isosteres as conformational probes for an isoprenyl subunit: application to inhibitors of squalene synthase. Bioorg Med Chem Lett, 3 (4): 595-600. DOI: 10.1016/S0960-894X(01)81236-1

3. Biller SA, Sofia MJ, DeLange B, Forster C, Gordon EM, Harrity T, Rich LC, Ciosek Jr CP. (1991) The First Potent Inhibitor of Squalene Synthase: A Profound Contribution of an Ether Oxygen to Inhibitor-Enzyme Interaction. J Am Chem Soc, 113 (22): 8522-8524. DOI: 10.1021/ja00022a050

4. Brinkman JA, Damon RE, Fell JB, Perez LB, Scallen TJ, Vedamanda TR. (1996) Squalene synthase inhibitors: isosteric replacements of the farnesyl chain of benzyl farnesyl amine. Bioorg Med Chem Lett, 6 (21): 2491-2494. DOI: 10.1016/0960-894X(96)00470-2

5. Brown GR, Butlin RJ, Chapman S, Eakin MA, Foubister AJ, Freeman S, Griffiths D, Harrison PJ, Johnson MC, Mallion KB. (1995) Phenoxypropylamines: a new series of squalene synthase inhibitors. J Med Chem, 38 (21): 4157-60. [PMID:7473541]

6. Brown GR, Clarke DS, Foubister AJ, Freeman S, Harrison PJ, Johnson MC, Mallion KB, McCormick J, McTaggart F, Reid AC et al.. (1996) Synthesis and activity of a novel series of 3-biarylquinuclidine squalene synthase inhibitors. J Med Chem, 39 (15): 2971-9. [PMID:8709131]

7. Brown GR, Foubister AJ, Freeman S, McTaggart F, Mirrlees DJ, Reid AC, Smith GJ, Taylor MJ, Thomason DA, Whittamore PRO. (1997) Novel optimised quinuclidine squalene synthase inhibitors. Bioorg Med Chem Lett, 7 (5): 597-600. DOI: 10.1016/S0960-894X(97)00053-X

8. Cammerer SB, Jimenez C, Jones S, Gros L, Lorente SO, Rodrigues C, Rodrigues JC, Caldera A, Ruiz Perez LM, da Souza W et al.. (2007) Quinuclidine derivatives as potential antiparasitics. Antimicrob Agents Chemother, 51 (11): 4049-61. [PMID:17709461]

9. Do R, Paré G, Montpetit A, Hudson TJ, Gaudet D, Engert JC. (2008) K45R variant of squalene synthase increases total cholesterol levels in two study samples from a French Canadian population. Hum Mutat, 29 (5): 689-94. [PMID:18350552]

10. Dufresne C, Wilson KE, Zink D, Smith J, Bergstrom JD, Kurtz M, Rew D, Nallin M, Jenkins R, Bartizal K, Trainor C, Bills G, Meinz M, Huang L, Onishi J, Milligan J, Mojena M, Pelaez F. (1992) The Isolation and Structure Elucidation of Zaragozic Acid C, a Novel Potent Squalene Synthase Inhibitor. Tetrahedron, 48 (41): 10221-10226.

11. Fung AK, Baker WR, Fakhoury S, Stein HH, Cohen J, Donner BG, Garvey DS, Spina KP, Rosenberg SH. (1997) (1 alpha, 2 beta, 3 beta, 4 alpha)-1,2-bis[N-propyl-N-(4-phenoxybenzyl) amino]carbonyl]cyclobutane-3,4-dicarboxylic acid (A-87049): a novel potent squalene synthase inhibitor. J Med Chem, 40 (14): 2123-5. [PMID:9216829]

12. Gotteland JP, Brunel I, Gendre F, Désiré J, Delhon A, Junquéro D, Oms P, Halazy S. (1995) (Aryloxy)methylsilane derivatives as new cholesterol biosynthesis inhibitors: synthesis and hypocholesterolemic activity of a new class of squalene epoxidase inhibitors. J Med Chem, 38 (17): 3207-16. [PMID:7650673]

13. Harris GH, Dufresne C, Joshua H, Koch LA, Zink DL, Salmon PM, Göklen KE, Kurtz MM, Rew DJ, Bergstrom JD, Wilson KE. (1995) Isolation, structure determination and squalene synthase activity of L-731,120 and L-731,128, alkyl citrate analogs of zaragozic acids A and B. Bioorg Med Chem Lett, 5 (20): 2403-2408.

14. Ichikawa M, Ohtsuka M, Ohki H, Haginoya N, Itoh M, Sugita K, Usui H, Suzuki M, Terayama K, Kanda A. (2012) Discovery of novel tricyclic compounds as squalene synthase inhibitors. Bioorg Med Chem, 20 (9): 3072-93. [PMID:22464687]

15. Ishihara T, Kakuta H, Moritani H, Ugawa T, Yanagisawa I. (2004) Synthesis and biological evaluation of novel propylamine derivatives as orally active squalene synthase inhibitors. Bioorg Med Chem, 12 (22): 5899-908. [PMID:15498666]

16. Iwasawa Y, Hayashi M, Nomoto T, Shibata J, Mitsuya M, Hirota K, Yonemoto M, Kamei T, Miura K, Tomimoto K. (1995) Synthesis and biological activity of J-104,118, a novel, potent inhibitor of squalene synthase. Bioorg Med Chem Lett, 5 (17): 1989-1994.

17. Iwasawa Y, Shibata J, Mitsuya M, Masaki H, Hayashi M, Kanno T, Sawasaki Y, Hisaka A, Kamei T, Tomimoto K. (1996) J-104,123, a novel and orally-active inhibitor of squalene synthase: Stereoselective synthesis and cholesterol lowering effects in dogs. Bioorg Med Chem Lett, 6 (4): 463-466.

18. Jiang G, McKenzie TL, Conrad DG, Shechter I. (1993) Transcriptional regulation by lovastatin and 25-hydroxycholesterol in HepG2 cells and molecular cloning and expression of the cDNA for the human hepatic squalene synthase. J Biol Chem, 268 (17): 12818-24. [PMID:7685352]

19. Kourounakis AP, Charitos C, Rekka EA, Kourounakis PN. (2008) Lipid-lowering (hetero)aromatic tetrahydro-1,4-oxazine derivatives with antioxidant and squalene synthase inhibitory activity. J Med Chem, 51 (18): 5861-5. [PMID:18754614]

20. Lin FY, Liu YL, Li K, Cao R, Zhu W, Axelson J, Pang R, Oldfield E. (2012) Head-to-head prenyl tranferases: anti-infective drug targets. J Med Chem, 55 (9): 4367-72. [PMID:22486710]

21. Liu CI, Jeng WY, Chang WJ, Ko TP, Wang AH. (2012) Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase. J Biol Chem, 287 (22): 18750-7. [PMID:22474324]

22. Lolli ML, Rolando B, Tosco P, Chaurasia S, Di Stilo A, Lazzarato L, Gorassini E, Ferracini R, Oliaro-Bosso S, Fruttero R et al.. (2010) Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs). Bioorg Med Chem, 18 (7): 2428-38. [PMID:20299227]

23. Magnin DR, Biller SA, Chen Y, Dickson JK, Fryszman OM, Lawrence RM, Logan JV, Sieber-McMaster ES, Sulsky RB, Traeger SC et al.. (1996) alpha-Phosphonosulfonic acids: potent and selective inhibitors of squalene synthase. J Med Chem, 39 (3): 657-60. [PMID:8576905]

24. Magnin DR, Biller SA, Dickson JK, Logan JV, Lawrence RM, Chen Y, Sulsky RB, Ciosek CP, Harrity TW, Jolibois KG. (1995) 1,1-Bisphosphonate squalene synthase inhibitors: interplay between the isoprenoid subunit and the diphosphate surrogate. J Med Chem, 38 (14): 2596-605. [PMID:7629799]

25. Miki T, Kori M, Mabuchi H, Tozawa R, Nishimoto T, Sugiyama Y, Teshima K, Yukimasa H. (2002) Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis. J Med Chem, 45 (20): 4571-80. [PMID:12238936]

26. Overhand M, Pieterman E, Cohen LH, Valentijn ARPM, van der Marel GA, van Boom JH. (1997) Synthesis of triphosphonate analogues of farnesyl pyrophosphate. Inhibitors of squalene synthase and protein:farnesyl transferase. Bioorg Med Chem Lett, 7 (18): 2435-2440.

27. Ponpipom MM, Girotra NN, Bugianesi RL, Roberts CD, Berger GD, Burk RM, Marquis RW, Parsons WH, Bartizal KF, Bergstom JD. (1994) Structure-activity relationships of C1 and C6 side chains of zaragozic acid A derivatives. J Med Chem, 37 (23): 4031-51. [PMID:7966163]

28. Prashad M. (1993) Amidinium cation as a mimic of allylic carbocation: synthesis and squalene synthetase inhibitory activity of an amidinium analog of a carbocation intermediate. J Med Chem, 36 (5): 631-2. [PMID:8496942]

29. Prashad M, Kathawala FG, Scallen T. (1993) N-(arylalkyl)farnesylamines: new potent squalene synthetase inhibitors. J Med Chem, 36 (10): 1501-4. [PMID:8496919]

30. Schechter I, Conrad DG, Hart I, Berger RC, McKenzie TL, Bleskan J, Patterson D. (1994) Localization of the squalene synthase gene (FDFT1) to human chromosome 8p22-p23.1. Genomics, 20 (1): 116-8. [PMID:8020937]

31. Sealey-Cardona M, Cammerer S, Jones S, Ruiz-Pérez LM, Brun R, Gilbert IH, Urbina JA, González-Pacanowska D. (2007) Kinetic characterization of squalene synthase from Trypanosoma cruzi: selective inhibition by quinuclidine derivatives. Antimicrob Agents Chemother, 51 (6): 2123-9. [PMID:17371809]

32. Seiki S, Frishman WH. (2009) Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia. Cardiol Rev, 17 (2): 70-6. [PMID:19367148]

33. Sharratt PJ, Hutson JL, Inglis GGA, Lester MG, Procopiou PA, Watson NS. (1994) Structurally simplified squalestatins: monocyclic 1,3-dioxane analogues. Bioorg Med Chem Lett, 4 (5): 661-666.

34. Shechter I, Gu P, Jiang G, Onofrey TJ, Cann RO, Castro A, Spencer TA. (1996) Sulfobetaine zwitterionic inhibitors of squalene synthase. Bioorg Med Chem Lett, 6 (21): 2585-2588.

35. Shechter I, Klinger E, Rucker ML, Engstrom RG, Spirito JA, Islam MA, Boettcher BR, Weinstein DB. (1992) Solubilization, purification, and characterization of a truncated form of rat hepatic squalene synthetase. J Biol Chem, 267 (12): 8628-35. [PMID:1569107]

36. Shen W, Garvey DS, Cohen J, Stein H, Rosenberg SH. (1998) Cyclopentanedi- and tricarboxylic acids as squalene synthase inhibitors: syntheses and evaluation. Bioorg Med Chem Lett, 8 (8): 891-6. [PMID:9871507]

37. Soltis DA, McMahon G, Caplan SL, Dudas DA, Chamberlin HA, Vattay A, Dottavio D, Rucker ML, Engstrom RG, Cornell-Kennon SA. (1995) Expression, purification, and characterization of the human squalene synthase: use of yeast and baculoviral systems. Arch Biochem Biophys, 316 (2): 713-23. [PMID:7864626]

38. Song Y, Lin FY, Yin F, Hensler M, Rodrígues Poveda CA, Mukkamala D, Cao R, Wang H, Morita CT, González Pacanowska D et al.. (2009) Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus. J Med Chem, 52 (4): 976-88. [PMID:19191557]

39. Song Y, Liu CI, Lin FY, No JH, Hensler M, Liu YL, Jeng WY, Low J, Liu GY, Nizet V et al.. (2009) Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results. J Med Chem, 52 (13): 3869-80. [PMID:19456099]

40. Thompson JF, Danley DE, Mazzalupo S, Milos PM, Lira ME, Harwood HJ. (1998) Truncation of human squalene synthase yields active, crystallizable protein. Arch Biochem Biophys, 350 (2): 283-90. [PMID:9473303]

41. Wattanasin S, Boettcher BR, Scallen T. (1997) N-Hydroxyglycine derivatives as novel inhibitors of squalene synthase. Bioorg Med Chem Lett, 7 (23): 3039-3044.

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