Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTFQEO5)

• DTT Name: Squalene synthetase (FDFT1)
• Synonyms: Squalene synthase; SS; SQS; Farnesyl-diphosphate farnesyltransferase; FPP:FPP farnesyltransferase
• Gene Name: FDFT1
• DTT Type: Discontinued target; [1]
• BioChemical Class: Alkyl aryl transferase
• UniProt ID: FDFT_HUMAN
• TTD ID: T81850
• EC Number: EC 2.5.1.21
• Sequence:
  MEFVKCLGHPEEFYNLVRFRIGGKRKVMPKMDQDSLSSSLKTCYKYLNQTSRSFAAVIQA
  LDGEMRNAVCIFYLVLRALDTLEDDMTISVEKKVPLLHNFHSFLYQPDWRFMESKEKDRQ
  VLEDFPTISLEFRNLAEKYQTVIADICRRMGIGMAEFLDKHVTSEQEWDKYCHYVAGLVG
  IGLSRLFSASEFEDPLVGEDTERANSMGLFLQKTNIIRDYLEDQQGGREFWPQEVWSRYV
  KKLGDFAKPENIDLAVQCLNELITNALHHIPDVITYLSRLRNQSVFNFCAIPQVMAIATL
  AACYNNQQVFKGAVKIRKGQAVTLMMDATNMPAVKAIIYQYMEEIYHRIPDSDPSSSKTR
  QIISTIRTQNLPNCQLISRSHYSPIYLSFVMLLAALSWQYLTTLSQVTEDYVQTGEH
• Function: Participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH.
• KEGG Pathway:
  Steroid biosynthesis (hsa00100)
  Metabolic pathways (hsa01100)
  Biosynthesis of antibiotics (hsa01130)
• Reactome Pathway:
  PPARA activates gene expression (R-HSA-1989781)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Cholesterol biosynthesis (R-HSA-191273)
• BioCyc Pathway: MetaCyc:HS01329-MON

Molecular Interaction Atlas (MIA) of This DTT

7 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Lapaquistat acetate	DMJY9CW	Hyperlipidaemia	5C80	Discontinued in Phase 3	[1]
BMS-187745	DMP8SIV	Hyperlipidaemia	5C80	Discontinued in Phase 2	[2]
SQ-32709	DMSQRXW	Arteriosclerosis	BD40	Discontinued in Phase 2	[3]
A-87049	DMUID46	N. A.	N. A.	Terminated	[4]
RPR-101821	DM21Y75	Arteriosclerosis	BD40	Terminated	[5]
SQ-34919	DMT7O9V	N. A.	N. A.	Terminated	[6]
Squalestatin 1	DM4JZPT	Arteriosclerosis	BD40	Terminated	[7]

67 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(Z)-3-[2-(9H-fluoren-2-yloxy)ethylidene]-quinuclidine hydrochloride 31	DMIQ14F	Discovery agent	N.A.	Investigative	[8]
1-allyl-2-[3-(isopropylamino)propoxy]-9H-carbazole	DMQJ9RZ	Discovery agent	N.A.	Investigative	[9]
1-allyl-2-[3-(isopropylamino)propoxy]-9H-xanthen-9-one	DMNDW4J	Discovery agent	N.A.	Investigative	[9]
2-[4-(2-Thienyl)phenyl]-4-methylmorpholin-2-ol	DM6R1XH	Discovery agent	N.A.	Investigative	[10]
3-[1'-{4'-(Benzyloxy)-phenyl}]-quinuclidine-2-ene	DMIHWAJ	Discovery agent	N.A.	Investigative	[11]
3-[7'-(Methoxy)-napht-2'-yl]-quinuclidine-2-ene	DM7IHUK	Discovery agent	N.A.	Investigative	[11]
BPH-652	DMX4WI7	Hypercholesterolaemia	5C80.0	Investigative	[12]
BPH-830	DM15L2J	Discovery agent	N.A.	Investigative	[13]
CP-294838	DM6BRLA	Discovery agent	N.A.	Investigative	[14]
E5700	DM8LPBF	Discovery agent	N.A.	Investigative	[15]
ER-119884	DMIQ801	Discovery agent	N.A.	Investigative	[15]
J-104118	DMQ8J3M	Discovery agent	N.A.	Investigative	[12]
J-104123	DMWF7RO	Discovery agent	N.A.	Investigative	[12]
L-731120	DM8WCUY	Discovery agent	N.A.	Investigative	[12]
L-731128	DMTHLUN	Discovery agent	N.A.	Investigative	[12]
L-735021	DM8BVJQ	Discovery agent	N.A.	Investigative	[16]
PMID12238936C3a	DMQZXMF	Discovery agent	N.A.	Investigative	[17]
PMID12238936C3f	DMO5J8N	Discovery agent	N.A.	Investigative	[17]
PMID17709461C4g	DMMB6NU	Discovery agent	N.A.	Investigative	[11]
PMID18754614C10	DM1JRGI	Discovery agent	N.A.	Investigative	[10]
PMID18754614C17	DMSVB9D	Discovery agent	N.A.	Investigative	[10]
PMID18754614C18	DMF7VZO	Discovery agent	N.A.	Investigative	[10]
PMID18754614C19	DMHSE96	Discovery agent	N.A.	Investigative	[10]
PMID18754614C4	DMQFYM4	Discovery agent	N.A.	Investigative	[10]
PMID18754614C7	DMVTLO0	Discovery agent	N.A.	Investigative	[10]
PMID18754614C8	DM7SCM3	Discovery agent	N.A.	Investigative	[10]
PMID18754614C9	DMPH7A6	Discovery agent	N.A.	Investigative	[10]
PMID19191557C14	DMG7D3I	Discovery agent	N.A.	Investigative	[2]
PMID19191557C19	DMXLVEC	Discovery agent	N.A.	Investigative	[2]
PMID19191557C21	DM5RIB0	Discovery agent	N.A.	Investigative	[2]
PMID19191557C3	DM1MEY3	Discovery agent	N.A.	Investigative	[2]
PMID19191557C32	DMH8QRI	Discovery agent	N.A.	Investigative	[2]
PMID19191557C35	DM09IEK	Discovery agent	N.A.	Investigative	[2]
PMID19191557C8	DMUWYA2	Discovery agent	N.A.	Investigative	[2]
PMID19456099C13	DMBU9E4	Discovery agent	N.A.	Investigative	[13]
PMID19456099C15	DMPZMS0	Discovery agent	N.A.	Investigative	[13]
PMID20299227C12	DMKAZ1O	Discovery agent	N.A.	Investigative	[18]
PMID20299227C20	DM9H6LZ	Discovery agent	N.A.	Investigative	[18]
PMID22464687C15a	DMCDOHA	Discovery agent	N.A.	Investigative	[19]
PMID7473541C11	DMB2MQW	Discovery agent	N.A.	Investigative	[20]
PMID7473541C19	DM2CP5J	Discovery agent	N.A.	Investigative	[20]
PMID7473541C20	DMMZ1LR	Discovery agent	N.A.	Investigative	[20]
PMID7473541C21	DMMRSZB	Discovery agent	N.A.	Investigative	[20]
PMID7629799C2d	DMOJ57D	Discovery agent	N.A.	Investigative	[21]
PMID7629799C2e	DMBRH0Q	Discovery agent	N.A.	Investigative	[21]
PMID7629799C6	DMXMF39	Discovery agent	N.A.	Investigative	[2]
PMID7650673C4q	DM5SU6N	Discovery agent	N.A.	Investigative	[22]
PMID7966163C3f	DMJF7OC	Discovery agent	N.A.	Investigative	[16]
PMID7966163C4e	DMD524S	Discovery agent	N.A.	Investigative	[16]
PMID7966163C6c	DMUEG8O	Discovery agent	N.A.	Investigative	[16]
PMID7966163C6d	DM0XU3C	Discovery agent	N.A.	Investigative	[16]
PMID7966163C6g	DM8T41N	Discovery agent	N.A.	Investigative	[16]
PMID8496919C7	DM8PBKQ	Discovery agent	N.A.	Investigative	[23]
PMID8576905C4	DMUJEA4	Discovery agent	N.A.	Investigative	[24]
PMID8709131C15	DMWBPOJ	Discovery agent	N.A.	Investigative	[25]
PMID8709131C17	DM10IQP	Discovery agent	N.A.	Investigative	[25]
PMID8709131C23	DMSKJ53	Discovery agent	N.A.	Investigative	[25]
PMID8709131C2a (+)	DM1OS6M	Discovery agent	N.A.	Investigative	[25]
PMID8709131C4	DMETC8A	Discovery agent	N.A.	Investigative	[25]
PMID9216829C5j	DM2F81A	Discovery agent	N.A.	Investigative	[4]
PMID9216829C5m	DM3ARWX	Discovery agent	N.A.	Investigative	[4]
PMID9871507C14	DMY28QM	Discovery agent	N.A.	Investigative	[26]
YM-75440	DMMCXWQ	Discovery agent	N.A.	Investigative	[9]
ZARAGOZIC ACID B	DMYRLA0	Discovery agent	N.A.	Investigative	[27]
Zaragozic Acid C	DMUQWP1	Discovery agent	N.A.	Investigative	[27]
Zaragozic Acid D	DMMTJE3	Discovery agent	N.A.	Investigative	[27]
Zaragozic Acid D2	DML4WQJ	Discovery agent	N.A.	Investigative	[27]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	4.16E-01	0.09	0.73
Familial hypercholesterolemia	5A11	Whole blood	7.85E-01	-0.09	-0.38

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Squalene synthase (FDFT1) DME Info
• Gene Name: FDFT1

1 Discontinued Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SQ-32709	DMSQRXW	Arteriosclerosis	BD40	Discontinued in Phase 2	[28]

References

• [1] Lapaquistat acetate, a squalene synthase inhibitor, changes macrophage/lipid-rich coronary plaques of hypercholesterolaemic rabbits into fibrous le... Br J Pharmacol. 2008 Jul;154(5):949-57.
• [2] Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in Staphylococcus aureus. J Med Chem. 2009 Feb 26;52(4):976-88.
• [3] Clinical pharmacokinetics and pharmacodynamics of a new squalene synthase inhibitor, BMS-188494, in healthy volunteers. J Clin Pharmacol. 1998 Dec;38(12):1116-21.
• [4] (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 ... J Med Chem. 1997 Jul 4;40(14):2123-5.
• [5] RPR 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.
• [6] Inhibition of farnesyl protein transferase by new farnesyl phosphonate derivatives of phenylalanine, Bioorg. Med. Chem. Lett. 6(12):1291-1296 (1996).
• [7] Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo. J Biol Chem. 1992 Jun 15;267(17):11705-8.
• [8] Syntheses and biological evaluation of novel quinuclidine derivatives as squalene synthase inhibitors. Bioorg Med Chem. 2003 May 29;11(11):2403-14.
• [9] Synthesis and biological evaluation of novel propylamine derivatives as orally active squalene synthase inhibitors. Bioorg Med Chem. 2004 Nov 15;12(22):5899-908.
• [10] Lipid-lowering (hetero)aromatic tetrahydro-1,4-oxazine derivatives with antioxidant and squalene synthase inhibitory activity. J Med Chem. 2008 Sep 25;51(18):5861-5.
• [11] Quinuclidine derivatives as potential antiparasitics. Antimicrob Agents Chemother. 2007 Nov;51(11):4049-61.
• [12] URL: 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).
• [13] Inhibition 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.
• [14] Truncation of human squalene synthase yields active, crystallizable protein. Arch Biochem Biophys. 1998 Feb 15;350(2):283-90.
• [15] Kinetic characterization of squalene synthase from Trypanosoma cruzi: selective inhibition by quinuclidine derivatives. Antimicrob Agents Chemother. 2007 Jun;51(6):2123-9.
• [16] Structure-activity relationships of C1 and C6 side chains of zaragozic acid A derivatives. J Med Chem. 1994 Nov 11;37(23):4031-51.
• [17] Synthesis 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.
• [18] Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs). Bioorg Med Chem. 2010 Apr 1;18(7):2428-38.
• [19] Discovery of novel tricyclic compounds as squalene synthase inhibitors. Bioorg Med Chem. 2012 May 1;20(9):3072-93.
• [20] Phenoxypropylamines: a new series of squalene synthase inhibitors. J Med Chem. 1995 Oct 13;38(21):4157-60.
• [21] 1,1-Bisphosphonate squalene synthase inhibitors: interplay between the isoprenoid subunit and the diphosphate surrogate. J Med Chem. 1995 Jul 7;38(14):2596-605.
• [22] (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.
• [23] N-(arylalkyl)farnesylamines: new potent squalene synthetase inhibitors. J Med Chem. 1993 May 14;36(10):1501-4.
• [24] Alpha-Phosphonosulfonic acids: potent and selective inhibitors of squalene synthase. J Med Chem. 1996 Feb 2;39(3):657-60.
• [25] Synthesis and activity of a novel series of 3-biarylquinuclidine squalene synthase inhibitors. J Med Chem. 1996 Jul 19;39(15):2971-9.
• [26] Cyclopentanedi- and tricarboxylic acids as squalene synthase inhibitors: syntheses and evaluation. Bioorg Med Chem Lett. 1998 Apr 21;8(8):891-6.
• [27] Zaragozic acids D and D2: potent inhibitors of squalene synthase and of Ras farnesyl-protein transferase. J Nat Prod. 1993 Nov;56(11):1923-9.
• [28] Increased activity of the sterol branch of the mevalonate pathway elevates glycosylation of secretory proteins and improves antifungal properties of Trichoderma atroviride. Fungal Genet Biol. 2020 Jan 17;137:103334.