Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMJZ0AM)

• Drug Name: GERANYLGERANYL DIPHOSPHATE Drug Info
• Synonyms: Geranylgeranyl pyrophosphate; Geranylgeranyl diphosphate; GGDP; 6699-20-3; geranylgeranyl-PP; GGPP; UNII-N21T0D88LX; (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl trihydrogen diphosphate; N21T0D88LX; Geranylgeraniol diphosphate; CHEBI:48861; all-trans-Geranylgeranyl pyrophosphate; all-trans-Geranylgeranyl diphosphate; Diphosphoric acid, mono(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl) ester, (E,E,E)-; Geranylgeranyl pyrophosphate ammonium salt; 2-trans,6-trans,10-trans-geranylgeranyl diphosphate

Indication

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[1]

• Cross-matching ID:
  PubChem CID: 447277
  ChEBI ID: CHEBI:48861
  CAS Number: CAS 6699-20-3
  TTD Drug ID: DMJZ0AM

Molecule-Related Drug Atlas

Drug(s) Targeting Farnesyl protein transferase (Ftase)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Lonafarnib	DMGM2Z6	Hutchinson-Gilford progeria syndrome	LD2B	Approved	[5]
Zarnestra	DMF30HL	Acute myeloid leukaemia	2A60	Phase 3	[6]
L-778123	DMWSC5L	Lymphoma	2A80-2A86	Phase 1	[7]
GGTI-2418	DM8U23L	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
BMS214662	DM5M48F	Non-small-cell lung cancer	2C25.Y	Phase 1	[9]
L-745631	DM4UP7R	Solid tumour/cancer	2A00-2F9Z	Terminated	[10]
ABT-839	DM4UN9A	Non-small-cell lung cancer	2C25.Y	Terminated	[11]
MANUMYCIN A	DM1SWOY	N. A.	N. A.	Terminated	[12]
SCH-44342	DMUL4VX	N. A.	N. A.	Terminated	[13]
RPR-113829	DMJ63GW	N. A.	N. A.	Terminated	[14]

Drug(s) Targeting CAAX farnesyltransferase beta (FNTB)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-745631	DM4UP7R	Solid tumour/cancer	2A00-2F9Z	Terminated	[10]
ABT-839	DM4UN9A	Non-small-cell lung cancer	2C25.Y	Terminated	[15]
MANUMYCIN A	DM1SWOY	N. A.	N. A.	Terminated	[12]
SCH-44342	DMUL4VX	N. A.	N. A.	Terminated	[10]
RPR-113829	DMJ63GW	N. A.	N. A.	Terminated	[14]
RPR-114334	DMAIJT6	N. A.	N. A.	Terminated	[14]
L-731735	DM1XBKC	Solid tumour/cancer	2A00-2F9Z	Terminated	[10]
FUSIDIENOL	DMI1Y92	N. A.	N. A.	Terminated	[16]
ABT-100	DMPFLS5	Solid tumour/cancer	2A00-2F9Z	Terminated	[17]
B-956	DM1IO9X	Solid tumour/cancer	2A00-2F9Z	Terminated	[18]

Drug(s) Targeting Geranyltranstransferase (FDPS)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Zoledronate	DMIXC7G	Adenocarcinoma	2D40	Approved	[19]
Minodronate	DM50PMY	Osteoporosis	FB83.0	Approved	[20]
Ibandronate	DM0QZBN	Hypercalcaemia	5B91.0	Approved	[19]
Alendronate	DMY2KX9	Bone Paget disease		Approved	[19]
Pamidronate	DMB4AVP	Bone Paget disease		Approved	[21]
Incadronate	DM3DSVJ	Hypercalcaemia	5B91.0	Approved	[22]
Risedronate	DM5FLTY	Bone Paget disease		Approved	[23]
NERIDRONIC ACID	DMMPG5V	Bone disease	FC0Z	Approved	[24]
Zarnestra	DMF30HL	Acute myeloid leukaemia	2A60	Phase 3	[25]
ISOPENTENYL PYROPHOSPHATE	DMTU05Y	Discovery agent	N.A.	Investigative	[2]

Drug(s) Affected By Mevalonate kinase (MVK)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Selenium	DM25CGV	N. A.	N. A.	Approved	[26]
Clavulanate	DM2FGRT	Bacteremia	1A73	Approved	[27]
Fluoxetine	DM3PD2C	Bipolar depression		Approved	[28]
obeticholic acid	DM3Q1SM	Primary biliary cholangitis	DB96.1	Approved	[29]
Troglitazone	DM3VFPD	Diabetic complication	5A2Y	Approved	[30]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[31]
Isotretinoin	DM4QTBN	Acne vulgaris	ED80	Approved	[32]
Ciclosporin	DMAZJFX	Graft-versus-host disease	4B24	Approved	[33]
Zoledronate	DMIXC7G	Adenocarcinoma	2D40	Approved	[34]
Dexamethasone	DMMWZET	Acute adrenal insufficiency		Approved	[35]

Drug(s) Affected By Geranylgeranyl pyrophosphate synthase (GGPS1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[36]
Selenium	DM25CGV	N. A.	N. A.	Approved	[26]
Isotretinoin	DM4QTBN	Acne vulgaris	ED80	Approved	[32]
Ciclosporin	DMAZJFX	Graft-versus-host disease	4B24	Approved	[37]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[38]
Zoledronate	DMIXC7G	Adenocarcinoma	2D40	Approved	[39]
Cupric Sulfate	DMP0NFQ	Fungal infection	1F29-1F2F	Approved	[40]
Arsenic	DMTL2Y1	N. A.	N. A.	Approved	[41]
Tocopherol	DMBIJZ6	N. A.	N. A.	Phase 2	[26]
Benzo(a)pyrene	DMN7J43	N. A.	N. A.	Phase 1	[42]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
CAAX farnesyltransferase beta (FNTB)	TT7WZIJ	FNTB_HUMAN	Inhibitor	[2]
Farnesyl protein transferase (Ftase)	TTXQKM3	FNTA_HUMAN; FNTB_HUMAN	Inhibitor	[2]
Geranyltranstransferase (FDPS)	TTIKWV4	FPPS_HUMAN	Inhibitor	[2]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Geranylgeranyl pyrophosphate synthase (GGPS1)	OTVEHG28	GGPPS_HUMAN	Gene/Protein Processing	[3]
Mevalonate kinase (MVK)	OTHJCUKT	KIME_HUMAN	Gene/Protein Processing	[4]

References

• [1] 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. (Ligand id: 3052).
• [2] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [3] Variously substituted (phosphonoacetamido)oxy analogues of geranylgeranyl diphosphate (GGdP) as GGdP-transferase (GGTase) inhibitors and antiproliferative agents. Med Chem. 2005 May;1(3):239-44. doi: 10.2174/1573406053765512.
• [4] Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways. J Lipid Res. 1997 Nov;38(11):2216-23.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [6] Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics. 2008 Sep;2(3):491-500.
• [7] Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein trans... Mol Cancer Ther. 2002 Jul;1(9):747-58.
• [8] Company report (Prescient)
• [9] Farnesyltransferase inhibitor BMS-214662 induces apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia. 2004 Oct;18(10):1599-604.
• [10] Ras farnesyltransferase: a new therapeutic target. J Med Chem. 1997 Sep 12;40(19):2971-90.
• [11] Aryl tetrahydropyridine inhibitors of farnesyltransferase: glycine, phenylalanine and histidine derivatives. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1359-62.
• [12] A novel metal-chelating inhibitor of protein farnesyltransferase. Bioorg Med Chem Lett. 2003 May 5;13(9):1523-6.
• [13] Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships. J Med Chem. 1999 Jun 17;42(12):2125-35.
• [14] Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase. J Med Chem. 1997 Jun 6;40(12):1763-7.
• [15] Design and synthesis of o-trifluoromethylbiphenyl substituted 2-amino-nicotinonitriles as inhibitors of farnesyltransferase. Bioorg Med Chem Lett. 2005 Jan 3;15(1):153-8.
• [16] Modeling of binding modes and inhibition mechanism of some natural ligands of farnesyl transferase using molecular docking. J Med Chem. 2002 Mar 28;45(7):1460-5.
• [17] Potent farnesyltransferase inhibitor ABT-100 abrogates acute allograft rejection. J Heart Lung Transplant. 2005 Sep;24(9):1403-9.
• [18] Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res. 1995 Nov 15;55(22):5310-4.
• [19] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [20] 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.
• [21] Detection of nonsterol isoprenoids by HPLC-MS/MS. Anal Biochem. 2008 Dec 1;383(1):18-24.
• [22] 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.
• [23] Activity of bisphosphonates against Trypanosoma brucei rhodesiense. J Med Chem. 2002 Jul 4;45(14):2904-14.
• [24] 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.
• [25] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [26] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [27] Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
• [28] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [29] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [30] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [31] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [32] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [33] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [34] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [35] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [36] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [37] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [38] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [39] Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. Biochem Biophys Res Commun. 2007 Feb 23;353(4):921-5. doi: 10.1016/j.bbrc.2006.12.094. Epub 2006 Dec 21.
• [40] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [41] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [42] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.