Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIKWV4)

• DTT Name: Geranyltranstransferase (FDPS)
• Synonyms: KIAA1293; Geranylgeranyl pyrophosphate synthase; Geranylgeranyl diphosphate synthase; GGPS1; GGPPSase; GGPP synthase; Farnesyltranstransferase; Farnesyl pyrophosphate synthase; Farnesyl diphosphate synthase; FPS protein; FPP synthase; Dimethylallyltranstransferase; (2E,6E)-farnesyl diphosphate synthase
• Gene Name: FDPS
• DTT Type: Successful target; [1]
• BioChemical Class: Alkyl aryl transferase
• UniProt ID: FPPS_HUMAN
• TTD ID: T86528
• EC Number: EC 2.5.1.10
• Sequence:
  MPLSRWLRSVGVFLLPAPYWAPRERWLGSLRRPSLVHGYPVLAWHSARCWCQAWTEEPRA
  LCSSLRMNGDQNSDVYAQEKQDFVQHFSQIVRVLTEDEMGHPEIGDAIARLKEVLEYNAI
  GGKYNRGLTVVVAFRELVEPRKQDADSLQRAWTVGWCVELLQAFFLVADDIMDSSLTRRG
  QICWYQKPGVGLDAINDANLLEACIYRLLKLYCREQPYYLNLIELFLQSSYQTEIGQTLD
  LLTAPQGNVDLVRFTEKRYKSIVKYKTAFYSFYLPIAAAMYMAGIDGEKEHANAKKILLE
  MGEFFQIQDDYLDLFGDPSVTGKIGTDIQDNKCSWLVVQCLQRATPEQYQILKENYGQKE
  AEKVARVKALYEELDLPAVFLQYEEDSYSHIMALIEQYAAPLPPAVFLGLARKIYKRRK
• Function: FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate. Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones.
• KEGG Pathway:
  Terpenoid backbone biosynthesis (hsa00900)
  Metabolic pathways (hsa01100)
  Biosynthesis of antibiotics (hsa01130)
• Reactome Pathway:
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Cholesterol biosynthesis (R-HSA-191273)
• BioCyc Pathway: MetaCyc:ENSG00000160752-MON

Molecular Interaction Atlas (MIA) of This DTT

8 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alendronate	DMY2KX9	Bone Paget disease		Approved	[2]
Ibandronate	DM0QZBN	Hypercalcaemia	5B91.0	Approved	[2]
Incadronate	DM3DSVJ	Hypercalcaemia	5B91.0	Approved	[3]
Minodronate	DM50PMY	Osteoporosis	FB83.0	Approved	[4]
NERIDRONIC ACID	DMMPG5V	Bone disease	FC0Z	Approved	[5]
Pamidronate	DMB4AVP	Bone Paget disease		Approved	[6]
Risedronate	DM5FLTY	Bone Paget disease		Approved	[7]
Zoledronate	DMIXC7G	Adenocarcinoma	2D40	Approved	[2]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Zarnestra	DMF30HL	Acute myeloid leukaemia	2A60	Phase 3	[8]

57 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(1-hydroxy-1-phosphono-heptyl)-phosphonic acid	DM5L8WX	Discovery agent	N.A.	Investigative	[9]
(2E, 6E)-farnesylbisphosphonate	DM3ST2Y	Discovery agent	N.A.	Investigative	[10]
(biphenyl-3-ylamino)methylenediphosphonic acid	DMGB97I	Discovery agent	N.A.	Investigative	[11]
1-(but-2-ylamino)ethyl 1,I-bisphosphonic acid	DMTMZAJ	Discovery agent	N.A.	Investigative	[9]
1-[(cyclohexylamino)ethyl]-1,1-bisphosphonicacid	DM1JQPW	Discovery agent	N.A.	Investigative	[9]
1-[(n-but-1-ylamino)ethyl]-1,1-bisphosphonic acid	DM8VNYA	Discovery agent	N.A.	Investigative	[9]
1-[(n-hex-1-ylamino)ethyl]-1,1-bisphosphonic acid	DM4ABTN	Discovery agent	N.A.	Investigative	[9]
1-[(n-oct-1-ylamino)ethyl]-1,1-bisphosphonic acid	DM9ZK0D	Discovery agent	N.A.	Investigative	[9]
1-[(prop-1-ylamino)ethyl]-1,1-bisphosphonic acid	DMCRHVI	Discovery agent	N.A.	Investigative	[9]
1-[(prop-2-ylamino)ethyl]-1,1-bisphosphonicacid	DMSCN8J	Discovery agent	N.A.	Investigative	[9]
1-[(tert-butylamino)ethyl]-1,1-bisphosphonicacid	DMLDY3H	Discovery agent	N.A.	Investigative	[9]
3-azageranylgeranyl diphosphate	DM6KNMB	Discovery agent	N.A.	Investigative	[12]
BPH-252	DMUOS3G	Discovery agent	N.A.	Investigative	[1]
BPH-608	DM0NQLI	Discovery agent	N.A.	Investigative	[13]
BPH-628	DM0TJ6R	Discovery agent	N.A.	Investigative	[1]
BPH-629	DM49BFM	Discovery agent	N.A.	Investigative	[13]
BPH-675	DM3IPYV	Discovery agent	N.A.	Investigative	[13]
BPH-676	DMPKAEW	Discovery agent	N.A.	Investigative	[13]
BPH-715	DMTHW3F	Discovery agent	N.A.	Investigative	[1]
BPH-742	DMD0XEO	Discovery agent	N.A.	Investigative	[1]
CT-10	DMIVNMJ	Solid tumour/cancer	2A00-2F9Z	Investigative	[14]
digeranyl bisphosphonate	DMXK8BH	Discovery agent	N.A.	Investigative	[1]
Dimethylallyl Diphosphate	DMP5I47	Discovery agent	N.A.	Investigative	[15]
diphosphoric acid	DMYWL89	Discovery agent	N.A.	Investigative	[5]
Geranyl Diphosphate	DMB9LE1	Discovery agent	N.A.	Investigative	[16]
GERANYLGERANYL DIPHOSPHATE	DMJZ0AM	Discovery agent	N.A.	Investigative	[15]
Homorisedronate	DMX8DC2	Discovery agent	N.A.	Investigative	[17]
ISOPENTENYL PYROPHOSPHATE	DMTU05Y	Discovery agent	N.A.	Investigative	[15]
Isopentyl Pyrophosphate	DM9J5IS	Discovery agent	N.A.	Investigative	[16]
NE-10575	DMGSNU4	Discovery agent	N.A.	Investigative	[5]
NE10790	DMVESO2	Discovery agent	N.A.	Investigative	[5]
NE11808	DMR92HV	Discovery agent	N.A.	Investigative	[5]
NE21650	DM58O3I	Discovery agent	N.A.	Investigative	[18]
NE58018	DM28ZPT	Discovery agent	N.A.	Investigative	[5]
NE58027	DMU4I8R	Discovery agent	N.A.	Investigative	[5]
NE58043	DMS7UNR	Discovery agent	N.A.	Investigative	[5]
NE58062	DMHIM6N	Discovery agent	N.A.	Investigative	[5]
NE97220	DMDWESP	Discovery agent	N.A.	Investigative	[5]
OLPADRONIC ACID SODIUM SALT	DM1XJBE	Bone resorption	FC0Z	Investigative	[19]
PG-1014491	DMH4AKG	Bone disease	FC0Z	Investigative	[14]
Piridronic acid	DMRDF8Z	Discovery agent	N.A.	Investigative	[5]
PMID12014956C12	DMFO7UC	Discovery agent	N.A.	Investigative	[12]
PMID17963374C31	DMTP5OY	Discovery agent	N.A.	Investigative	[20]
PMID17975902C5e	DMS1QM8	Discovery agent	N.A.	Investigative	[21]
PMID18295483C2	DM3GYNM	Discovery agent	N.A.	Investigative	[22]
PMID18800762C11	DM4UWKR	Discovery agent	N.A.	Investigative	[1]
PMID18800762C14	DM5T2FR	Discovery agent	N.A.	Investigative	[1]
PMID18800762C16	DM70SEQ	Discovery agent	N.A.	Investigative	[1]
PMID18800762C19	DM1QXFI	Discovery agent	N.A.	Investigative	[1]
PMID18800762C47	DMZDC14	Discovery agent	N.A.	Investigative	[1]
PMID18800762C51	DMWFGY4	Discovery agent	N.A.	Investigative	[1]
[2-(6-Chloro-purin-9-yl)ethyl]-bisphosphonic acid	DM5LVIR	Discovery agent	N.A.	Investigative	[23]
[2-(Benzoimidazol-1-yl)ethyl]-bisphosphonic acid	DM98MXT	Discovery agent	N.A.	Investigative	[23]
[2-(Imidazol-1-yl)ethyl]-bisphosphonic acid	DMQZUD9	Discovery agent	N.A.	Investigative	[23]
[2-(Imidazol-2-yl-thio)ethyl]-bisphosphonic acid	DMBVDY5	Discovery agent	N.A.	Investigative	[23]
[2-(Purin-9-yl)ethyl]-bisphosphonic acid	DM3VT8M	Discovery agent	N.A.	Investigative	[23]
[2-(Pyrazol-1-yl)ethyl]-bisphosphonic acid	DMJN8XK	Discovery agent	N.A.	Investigative	[23]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Osteoporosis	FA20	Bone marrow	7.06E-03	-0.73	-2.57

References

• [1] Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J Med Chem. 2008 Sep 25;51(18):5594-607.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001 Feb;296(2):235-42.
• [4] Synthesis, chiral high performance liquid chromatographic resolution and enantiospecific activity of a potent new geranylgeranyl transferase inhibitor, 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid. J Med Chem. 2010 May 13;53(9):3454-64.
• [5] Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of hu... J Med Chem. 2008 Apr 10;51(7):2187-95.
• [6] Detection of nonsterol isoprenoids by HPLC-MS/MS. Anal Biochem. 2008 Dec 1;383(1):18-24.
• [7] Activity of bisphosphonates against Trypanosoma brucei rhodesiense. J Med Chem. 2002 Jul 4;45(14):2904-14.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Synthesis and biological evaluation of 2-alkylaminoethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii targeting farnesyl... Bioorg Med Chem. 2008 Mar 15;16(6):3283-90.
• [10] Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors. Bioorg Med Chem. 2008 Jan 1;16(1):390-9.
• [11] Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: a QSAR i... Bioorg Med Chem. 2008 Oct 1;16(19):8959-67.
• [12] Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates and diphosphates: a potential route to new bone antiresorption and antiparasitic agents. J Med Chem. 2002 May 23;45(11):2185-96.
• [13] Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7.
• [14] 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: 643).
• [15] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [16] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [17] Bisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase. J Biol Chem. 2001 Sep 7;276(36):33930-7.
• [18] Identification of a bisphosphonate that inhibits isopentenyl diphosphate isomerase and farnesyl diphosphate synthase. Biochem Biophys Res Commun. 2002 Jan 18;290(2):869-73.
• [19] Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo. Biochem Biophys Res Commun. 1999 Feb 16;255(2):491-4.
• [20] Activity of sulfonium bisphosphonates on tumor cell lines. J Med Chem. 2007 Nov 29;50(24):6067-79.
• [21] Synthesis and biological evaluation of alpha-halogenated bisphosphonate and phosphonocarboxylate analogues of risedronate. J Med Chem. 2007 Nov 29;50(24):5967-75.
• [22] Design and structure-activity relationships of potent and selective inhibitors of undecaprenyl pyrophosphate synthase (UPPS): tetramic, tetronic acids and dihydropyridin-2-ones. Bioorg Med Chem Lett.2008 Mar 15;18(6):1840-4.
• [23] Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocy... J Med Chem. 2008 Nov 13;51(21):6800-7.