squalene synthase | Lanosterol biosynthesis pathway | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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squalene synthase

Target id: 645

Nomenclature: squalene synthase

Family: Lanosterol biosynthesis pathway

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 417 8p23.1-p22 FDFT1 farnesyl-diphosphate farnesyltransferase 1 30
Mouse - 416 14 D1; 14 3.0 cM Fdft1 farnesyl diphosphate farnesyl transferase 1
Rat - 416 15p12 Fdft1 farnesyl diphosphate farnesyl transferase 1
Previous and Unofficial Names
farnesyltransferase | FDFT1 | presqualene synthase | presqualene-diphosphate synthase | SQS | squalene synthetase | SSase | FPP:FPP farnesyltransferase
Database Links
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CATH/Gene3D
ChEMBL Target
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Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
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
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
Substrate Sp. Property Value Units Standard property Standard value Assay description Assay conditions Comments Reference
NADPH 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 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 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 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 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 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
Cofactor Species Comments Reference
Mg2+ Human 32
NADPH Human 32
NADH Human 32

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Inhibitors
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Ligand Sp. Action Value Parameter Reference
zaragozic acid B 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 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 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 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] 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] 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] 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] 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 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] 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 Hs Inhibition 6.1 pKi 20
pKi 6.1 (Ki 7.4x10-7 M) [20]
compound 21 [PMID: 7473541] 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] 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] 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] 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] 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] 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] 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] 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] 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 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] 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] 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 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 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] 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] 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 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] Hs Inhibition 8.9 pIC50 14
pIC50 8.9 (IC50 1.3x10-9 M) [14]
E5700 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] 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] Rn Inhibition 8.6 pIC50 24
pIC50 8.6 (IC50 2.5x10-9 M) [24]
Description: Inhibition rat liver microsomal squalene synthase
J-104123 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] Hs Inhibition 7.7 pIC50 26
pIC50 7.7 (IC50 1.8x10-8 M) [26]
Description: Inhibition of Squalene Synthase
NB-598 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 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] 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 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 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 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 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] 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 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] 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] 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 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 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] 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 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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
Liver
Species:  Human
Technique:  Northern blot
References:  18
Clinically-Relevant Mutations and Pathophysiology
Disease:  Recombinant chromosome 8 syndrome
OMIM: 179613
Biologically Significant Variants
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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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]

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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]

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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]

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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]

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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]

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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]

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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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