Target Information
| Target General Information | Top | |||||
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| Target ID |
T76396
(Former ID: TTDR00229)
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| Target Name |
Geranylgeranyl transferase I (GGTase-I)
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| Synonyms |
Type I protein geranyl-geranyltransferase subunit beta; Type I protein geranyl-geranyltransferase beta subunit of Saccharomyces cerevisiae; RAS proteins geranylgeranyltransferase beta subunit; PGGT; Geranylgeranyl transferase type-1 subunit beta; Geranylgeranyl transferase type I subunit beta; GGTase-I-beta of Saccharomyces cerevisiae; GGTase-I-beta; CDC43
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| Gene Name |
PGGT1B
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Lymphoma [ICD-11: 2A80-2A86] | |||||
| Function |
Catalyzes the transfer of a geranyl-geranyl moiety from geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. Known substrates include RAC1, RAC2, RAP1A and RAP1B.
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| BioChemical Class |
Alkyl aryl transferase
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| UniProt ID | ||||||
| EC Number |
EC 2.5.1.59
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| Sequence |
MAATEDERLAGSGEGERLDFLRDRHVRFFQRCLQVLPERYSSLETSRLTIAFFALSGLDM
LDSLDVVNKDDIIEWIYSLQVLPTEDRSNLNRCGFRGSSYLGIPFNPSKAPGTAHPYDSG HIAMTYTGLSCLVILGDDLSRVNKEACLAGLRALQLEDGSFCAVPEGSENDMRFVYCASC ICYMLNNWSGMDMKKAITYIRRSMSYDNGLAQGAGLESHGGSTFCGIASLCLMGKLEEVF SEKELNRIKRWCIMRQQNGYHGRPNKPVDTCYSFWVGATLKLLKIFQYTNFEKNRNYILS TQDRLVGGFAKWPDSHPDALHAYFGICGLSLMEESGICKVHPALNVSTRTSERLLDLHQS WKTKDSKQCSENVHIST Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | L-778123 | Drug Info | Phase 1 | Lymphoma | [2], [3] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | L-745631 | Drug Info | Terminated | Solid tumour/cancer | [4] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | L-778123 | Drug Info | [1] | |||
| Inhibitor | [+] 6 Inhibitor drugs | + | ||||
| 1 | GGTI-298 | Drug Info | [5] | |||
| 2 | L-745631 | Drug Info | [6] | |||
| 3 | A-313326 | Drug Info | [7] | |||
| 4 | J-109,390 | Drug Info | [8] | |||
| 5 | L-269,289 | Drug Info | [8] | |||
| 6 | PD-83176 | Drug Info | [9] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.72E-01 | Radiality | 1.27E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 6.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| References | Top | |||||
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| REF 1 | 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. | |||||
| REF 2 | ClinicalTrials.gov (NCT00003430) L-778,123 in Treating Patients With Recurrent or Refractory Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 3 | A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clin Cancer Res. 2004 Aug 15;10(16):5447-54. | |||||
| REF 4 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007537) | |||||
| REF 5 | The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J Biol Chem. 1997 Oct 24;272(43):27224-9. | |||||
| REF 6 | Ras farnesyltransferase: a new therapeutic target. J Med Chem. 1997 Sep 12;40(19):2971-90. | |||||
| REF 7 | 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. | |||||
| REF 8 | Geranylgeranyltransferase I of Candida albicans: null mutants or enzyme inhibitors produce unexpected phenotypes. J Bacteriol. 2000 Feb;182(3):704-13. | |||||
| REF 9 | Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. J Med Chem. 1997 Jan 17;40(2):192-200. | |||||
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