Target Information

Target General Infomation
Target ID
T81850
Former ID
TTDC00106
Target Name
Squalene synthetase
Gene Name
FDFT1
Synonyms
FPP:FPP farnesyltransferase; SQS; SS; Squalene synthase; Squalene synthetase; FDFT1
Target Type
Discontinued
Disease Arteriosclerosis [ICD9: 440; ICD10: I70]
Hyperlipidaemia [ICD9: 272.0-272.4; ICD10: E78]
Hypercholesterolemia [ICD10: E78]
BioChemical Class
Alkyl aryl transferase
Target Validation
T81850
UniProt ID
P37268
EC Number
EC 2.5.1.21
Sequence
MEFVKCLGHPEEFYNLVRFRIGGKRKVMPKMDQDSLSSSLKTCYKYLNQTSRSFAAVIQA
LDGEMRNAVCIFYLVLRALDTLEDDMTISVEKKVPLLHNFHSFLYQPDWRFMESKEKDRQ
VLEDFPTISLEFRNLAEKYQTVIADICRRMGIGMAEFLDKHVTSEQEWDKYCHYVAGLVG
IGLSRLFSASEFEDPLVGEDTERANSMGLFLQKTNIIRDYLEDQQGGREFWPQEVWSRYV
KKLGDFAKPENIDLAVQCLNELITNALHHIPDVITYLSRLRNQSVFNFCAIPQVMAIATL
AACYNNQQVFKGAVKIRKGQAVTLMMDATNMPAVKAIIYQYMEEIYHRIPDSDPSSSKTR
QIISTIRTQNLPNCQLISRSHYSPIYLSFVMLLAALSWQYLTTLSQVTEDYVQTGEH
Drugs and Mode of Action
Drug(s) Lapaquistat acetate Drug Info Discontinued in Phase 3 Hyperlipidaemia [522119]
BMS-187745 Drug Info Discontinued in Phase 2 Hyperlipidaemia [531655]
SQ-32709 Drug Info Discontinued in Phase 2 Arteriosclerosis [545908]
A-87049 Drug Info Terminated Discovery agent [546182]
RPR-101821 Drug Info Terminated Arteriosclerosis [546131]
SQ-34919 Drug Info Terminated Discovery agent [540105], [545851]
Squalestatin 1 Drug Info Terminated Arteriosclerosis [540059], [545281]
Inhibitor (Z)-3-[2-(9H-fluoren-2-yloxy)ethylidene]-quinuclidine hydrochloride 31 Drug Info [535732]
1-allyl-2-[3-(isopropylamino)propoxy]-9H-carbazole Drug Info [527258]
1-allyl-2-[3-(isopropylamino)propoxy]-9H-xanthen-9-one Drug Info [527258]
2-[4-(2-Thienyl)phenyl]-4-methylmorpholin-2-ol Drug Info [529661]
3-[1'-{4'-(Benzyloxy)-phenyl}]-quinuclidine-2-ene Drug Info [528993]
3-[7'-(Methoxy)-napht-2'-yl]-quinuclidine-2-ene Drug Info [528993]
A-87049 Drug Info [534419]
BMS-187745 Drug Info [529947]
BPH-652 Drug Info [543910]
BPH-830 Drug Info [530152]
compound 1 Drug Info [534061]
compound 1 (Overhand et al., 1997) Drug Info [543910]
compound 10 Drug Info [529661]
compound 11 Drug Info [533586]
compound 12 Drug Info [530797]
compound 12 (Wattanasin et al.,1997) Drug Info [543910]
compound 13 Drug Info [530152]
compound 14 Drug Info [529947]
compound 14 Drug Info [534782]
compound 15 Drug Info [530152]
compound 15 Drug Info [534158]
compound 15 (Biller et al., 1993) Drug Info [543910]
compound 15a Drug Info [531861]
compound 16a (Sharratt et al., 1994) Drug Info [543910]
compound 17 Drug Info [534158]
compound 17 Drug Info [529661]
compound 17 (Shechter et al., 1996) Drug Info [543910]
compound 18 Drug Info [529661]
compound 19 Drug Info [529661]
compound 19 Drug Info [529947]
compound 19 Drug Info [533586]
compound 1c (Brown et al., 1997) Drug Info [543910]
compound 1e (Brown et al., 1997) Drug Info [543910]
compound 20 Drug Info [530797]
compound 20 Drug Info [533586]
compound 20 (Shechter et al., 1996) Drug Info [543910]
compound 21 Drug Info [529947]
compound 21 Drug Info [533586]
compound 23 Drug Info [534158]
compound 28 Drug Info [533586]
compound 2a (+) Drug Info [534158]
compound 2d Drug Info [533667]
compound 2e Drug Info [533667]
compound 3 Drug Info [529947]
compound 32 Drug Info [529947]
compound 35 Drug Info [529947]
compound 3a Drug Info [526429]
compound 3f Drug Info [526429]
compound 3f Drug Info [533824]
compound 4 Drug Info [529661]
compound 4 Drug Info [534096]
compound 4 Drug Info [534158]
compound 4 (Brinkman et al., 1996) Drug Info [543910]
compound 4e Drug Info [533824]
compound 4g Drug Info [528993]
compound 4q Drug Info [533676]
compound 5 Drug Info [529661]
compound 5d Drug Info [533824]
compound 5j Drug Info [534419]
compound 5m Drug Info [534419]
compound 6 Drug Info [529947]
compound 6 (Biller et al., 1991) Drug Info [543910]
compound 6c Drug Info [533824]
compound 6d Drug Info [533824]
compound 6g Drug Info [533824]
compound 7 Drug Info [529661]
compound 7 Drug Info [534058]
compound 7 (Brinkman et al., 1996) Drug Info [543910]
compound 8 Drug Info [529661]
compound 8 Drug Info [529947]
compound 8 (Brinkman et al., 1996) Drug Info [543910]
compound 9 Drug Info [529661]
CP-294838 Drug Info [534560]
E5700 Drug Info [528739]
ER-119884 Drug Info [528739]
J-104118 Drug Info [543910]
J-104123 Drug Info [543910]
L-731120 Drug Info [543910]
L-731128 Drug Info [543910]
L-735021 Drug Info [533824]
Lapaquistat acetate Drug Info [536444], [536754]
N-hydroxyglycine derivative Drug Info [551333]
SQ-34919 Drug Info [551299]
YM-75440 Drug Info [527258]
ZARAGOZIC ACID B Drug Info [551358]
Zaragozic Acid C Drug Info [551358]
Zaragozic Acid D Drug Info [551358]
Zaragozic Acid D2 Drug Info [551358]
ZARAGOZIC ACIDS A Drug Info [551358]
Zwitterionic sulfobetaine derivative Drug Info [551306]
Modulator RPR-101821 Drug Info [534162]
SQ-32709 Drug Info [526027]
Squalestatin 1 Drug Info [527638]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
BioCyc Pathway Cholesterol biosynthesis II (via 24,25-dihydrolanosterol)
Cholesterol biosynthesis III (via desmosterol)
Cholesterol biosynthesis I
Superpathway of cholesterol biosynthesis
Epoxysqualene biosynthesis
KEGG Pathway Steroid biosynthesis
Metabolic pathways
Biosynthesis of antibiotics
PANTHER Pathway Cholesterol biosynthesis
PathWhiz Pathway Steroid Biosynthesis
Reactome Cholesterol biosynthesis
PPARA activates gene expression
Activation of gene expression by SREBF (SREBP)
WikiPathways Statin Pathway
Regulation of Lipid Metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
Activation of Gene Expression by SREBP (SREBF)
SREBP signalling
Cholesterol Biosynthesis
Cholesterol biosynthesis
References
Ref 522119ClinicalTrials.gov (NCT00532558) Efficacy of Lapaquistat Acetate on Blood Cholesterol Levels in Treating Subjects With Hypercholesterolemia. U.S. National Institutes of Health.
Ref 531655Potential role of nonstatin cholesterol lowering agents. IUBMB Life. 2011 Nov;63(11):964-71.
Ref 540059(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3057).
Ref 540105(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3101).
Ref 545281Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002681)
Ref 545851Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005042)
Ref 545908Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005302)
Ref 546131Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006470)
Ref 546182Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006785)
Ref 526027Clinical pharmacokinetics and pharmacodynamics of a new squalene synthase inhibitor, BMS-188494, in healthy volunteers. J Clin Pharmacol. 1998 Dec;38(12):1116-21.
Ref 526429Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis. J Med Chem. 2002 Sep 26;45(20):4571-80.
Ref 527258Synthesis and biological evaluation of novel propylamine derivatives as orally active squalene synthase inhibitors. Bioorg Med Chem. 2004 Nov 15;12(22):5899-908.
Ref 527638Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo. J Biol Chem. 1992 Jun 15;267(17):11705-8.
Ref 528739Antimicrob Agents Chemother. 2007 Jun;51(6):2123-9. Epub 2007 Mar 19.Kinetic characterization of squalene synthase from Trypanosoma cruzi: selective inhibition by quinuclidine derivatives.
Ref 528993Antimicrob Agents Chemother. 2007 Nov;51(11):4049-61. Epub 2007 Aug 20.Quinuclidine derivatives as potential antiparasitics.
Ref 529661J Med Chem. 2008 Sep 25;51(18):5861-5.Lipid-lowering (hetero)aromatic tetrahydro-1,4-oxazine derivatives with antioxidant and squalene synthase inhibitory activity.
Ref 529947J Med Chem. 2009 Feb 26;52(4):976-88.Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus.
Ref 530152Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: in vitro, in vivo, and crystallographic results. J Med Chem. 2009 Jul 9;52(13):3869-80.
Ref 530797Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs). Bioorg Med Chem. 2010 Apr 1;18(7):2428-38.
Ref 531861Discovery of novel tricyclic compounds as squalene synthase inhibitors. Bioorg Med Chem. 2012 May 1;20(9):3072-93.
Ref 533586Phenoxypropylamines: a new series of squalene synthase inhibitors. J Med Chem. 1995 Oct 13;38(21):4157-60.
Ref 5336671,1-Bisphosphonate squalene synthase inhibitors: interplay between the isoprenoid subunit and the diphosphate surrogate. J Med Chem. 1995 Jul 7;38(14):2596-605.
Ref 533676(Aryloxy)methylsilane derivatives as new cholesterol biosynthesis inhibitors: synthesis and hypocholesterolemic activity of a new class of squalene epoxidase inhibitors. J Med Chem. 1995 Aug 18;38(17):3207-16.
Ref 533824Structure-activity relationships of C1 and C6 side chains of zaragozic acid A derivatives. J Med Chem. 1994 Nov 11;37(23):4031-51.
Ref 534058N-(arylalkyl)farnesylamines: new potent squalene synthetase inhibitors. J Med Chem. 1993 May 14;36(10):1501-4.
Ref 534061Amidinium cation as a mimic of allylic carbocation: synthesis and squalene synthetase inhibitory activity of an amidinium analog of a carbocation intermediate. J Med Chem. 1993 Mar 5;36(5):631-2.
Ref 534096Alpha-Phosphonosulfonic acids: potent and selective inhibitors of squalene synthase. J Med Chem. 1996 Feb 2;39(3):657-60.
Ref 534158Synthesis and activity of a novel series of 3-biarylquinuclidine squalene synthase inhibitors. J Med Chem. 1996 Jul 19;39(15):2971-9.
Ref 534162RPR 101821, a new potent cholesterol-lowering agent: inhibition of squalene synthase and 7-dehydrocholesterol reductase. Naunyn Schmiedebergs Arch Pharmacol. 1996 Jan;353(2):233-40.
Ref 534419J Med Chem. 1997 Jul 4;40(14):2123-5.(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.
Ref 534560Truncation of human squalene synthase yields active, crystallizable protein. Arch Biochem Biophys. 1998 Feb 15;350(2):283-90.
Ref 534782Cyclopentanedi- and tricarboxylic acids as squalene synthase inhibitors: syntheses and evaluation. Bioorg Med Chem Lett. 1998 Apr 21;8(8):891-6.
Ref 535732Syntheses and biological evaluation of novel quinuclidine derivatives as squalene synthase inhibitors. Bioorg Med Chem. 2003 May 29;11(11):2403-14.
Ref 536444Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs. Toxicol Appl Pharmacol. 2007 Aug 15;223(1):39-45. Epub 2007 May 24.
Ref 536754Lapaquistat acetate, a squalene synthase inhibitor, changes macrophage/lipid-rich coronary plaques of hypercholesterolaemic rabbits into fibrous lesions. Br J Pharmacol. 2008 Jul;154(5):949-57. Epub2008 Apr 21.
Ref 543910(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 645).
Ref 551299Inhibition of farnesyl protein transferase by new farnesyl phosphonate derivatives of phenylalanine, Bioorg. Med. Chem. Lett. 6(12):1291-1296 (1996).
Ref 551306Sulfobetaine zwitterionic inhibitors of squalene synthase, Bioorg. Med. Chem. Lett. 6(21):2585-2588 (1996).
Ref 551333N-Hydroxyglycine derivatives as novel inhibitors of squalene synthase, Bioorg. Med. Chem. Lett. 7(23):3039-3044 (1997).
Ref 551358Zaragozic acids D and D2: potent inhibitors of squalene synthase and of Ras farnesyl-protein transferase. J Nat Prod. 1993 Nov;56(11):1923-9.

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