Target Information
| Target General Information | Top | |||||
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| Target ID |
T86428
(Former ID: TTDR01076)
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| Target Name |
CAAX farnesyltransferase beta (FNTB)
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| Synonyms |
RAS proteins prenyltransferasebeta; FTase-beta; FNTB; CAAX farnesyltransferase beta subunit
Click to Show/Hide
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| Gene Name |
FNTB
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Colorectal cancer [ICD-11: 2B91] | |||||
| 2 | Lung cancer [ICD-11: 2C25] | |||||
| 3 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Essential subunit of the farnesyltransferase complex. Catalyzes the transfer of a farnesyl moiety from farnesyl diphosphate to a cysteine at the fourth position from the C- terminus of several proteins having the C-terminal sequence Cys- aliphatic-aliphatic-X.
Click to Show/Hide
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| BioChemical Class |
Alkyl aryl transferase
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| UniProt ID | ||||||
| EC Number |
EC 2.5.1.58
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| Sequence |
MASPSSFTYYCPPSSSPVWSEPLYSLRPEHARERLQDDSVETVTSIEQAKVEEKIQEVFS
SYKFNHLVPRLVLQREKHFHYLKRGLRQLTDAYECLDASRPWLCYWILHSLELLDEPIPQ IVATDVCQFLELCQSPEGGFGGGPGQYPHLAPTYAAVNALCIIGTEEAYDIINREKLLQY LYSLKQPDGSFLMHVGGEVDVRSAYCAASVASLTNIITPDLFEGTAEWIARCQNWEGGIG GVPGMEAHGGYTFCGLAALVILKRERSLNLKSLLQWVTSRQMRFEGGFQGRCNKLVDGCY SFWQAGLLPLLHRALHAQGDPALSMSHWMFHQQALQEYILMCCQCPAGGLLDKPGKSRDF YHTCYCLSGLSIAQHFGSGAMLHDVVLGVPENALQPTHPVYNIGPDKVIQATTYFLQKPV PGFEELKDETSAEPATD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Discontinued Drug(s) | [+] 12 Discontinued Drugs | + | ||||
| 1 | ABT-100 | Drug Info | Terminated | Solid tumour/cancer | [2] | |
| 2 | ABT-839 | Drug Info | Terminated | Non-small-cell lung cancer | [3] | |
| 3 | B-956 | Drug Info | Terminated | Solid tumour/cancer | [4] | |
| 4 | BMS-182566 | Drug Info | Terminated | Solid tumour/cancer | [5] | |
| 5 | BMS-185857 | Drug Info | Terminated | Solid tumour/cancer | [6] | |
| 6 | CP-663427 | Drug Info | Terminated | Solid tumour/cancer | [7] | |
| 7 | L-731735 | Drug Info | Terminated | Solid tumour/cancer | [8] | |
| 8 | L-739749 | Drug Info | Terminated | Solid tumour/cancer | [9] | |
| 9 | L-745631 | Drug Info | Terminated | Solid tumour/cancer | [10] | |
| 10 | Sch-207758 | Drug Info | Terminated | Solid tumour/cancer | [11] | |
| 11 | XR-3005 | Drug Info | Terminated | Colorectal cancer | [12] | |
| 12 | XR-3054 | Drug Info | Terminated | Solid tumour/cancer | [13] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 35 Inhibitor drugs | + | ||||
| 1 | ABT-100 | Drug Info | [14] | |||
| 2 | ABT-839 | Drug Info | [15] | |||
| 3 | CP-663427 | Drug Info | [16] | |||
| 4 | FUSIDIENOL | Drug Info | [17] | |||
| 5 | L-731735 | Drug Info | [18] | |||
| 6 | L-739749 | Drug Info | [18] | |||
| 7 | L-745631 | Drug Info | [18] | |||
| 8 | MANUMYCIN A | Drug Info | [19] | |||
| 9 | RPR-113829 | Drug Info | [20] | |||
| 10 | RPR-114334 | Drug Info | [20] | |||
| 11 | Sch-207758 | Drug Info | [21] | |||
| 12 | SCH-44342 | Drug Info | [18] | |||
| 13 | XR-3054 | Drug Info | [13] | |||
| 14 | (Z)-2-Methyl-3-tetradecyl-but-2-enedioic acid | Drug Info | [18] | |||
| 15 | A-313326 | Drug Info | [15] | |||
| 16 | ACTINOPLANIC ACID A | Drug Info | [18] | |||
| 17 | ALPHA-HYDROXYFARNESYLPHOSPHONIC ACID | Drug Info | [22] | |||
| 18 | Arteminolide | Drug Info | [17] | |||
| 19 | BMS-316810 | Drug Info | [23] | |||
| 20 | BMS-404683 | Drug Info | [24] | |||
| 21 | CLAVARINONE | Drug Info | [25] | |||
| 22 | CYLINDROL A | Drug Info | [18] | |||
| 23 | F-12458 | Drug Info | [26] | |||
| 24 | FARNESYL | Drug Info | [22] | |||
| 25 | FTI 276 | Drug Info | [27] | |||
| 26 | GERANYLGERANYL DIPHOSPHATE | Drug Info | [22] | |||
| 27 | H-SMGLPCVVM-OH | Drug Info | [28] | |||
| 28 | L-739750 | Drug Info | [18] | |||
| 29 | LB42908 | Drug Info | [29] | |||
| 30 | PB-27 | Drug Info | [24] | |||
| 31 | PB-80 | Drug Info | [24] | |||
| 32 | PB-81 | Drug Info | [24] | |||
| 33 | PD-83176 | Drug Info | [30] | |||
| 34 | Prenyl pyrophosphate analogue | Drug Info | [31] | |||
| 35 | PREUSSOMERIN | Drug Info | [18] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | B-956 | Drug Info | [4] | |||
| 2 | BMS-182566 | Drug Info | [1] | |||
| 3 | BMS-185857 | Drug Info | [1] | |||
| 4 | XR-3005 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Zarnestra | Ligand Info | |||||
| Structure Description | human protein farnesyltransferase complexed with FPP and R115777 | PDB:1SA4 | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [32] |
| PDB Sequence |
SSPVWSEPLY
24 SLRPEHARER34 LQDDSVETVT44 SIEQAKVEEK54 IQEVFSSYKF64 NHLVPRLVLQ 74 REKHFHYLKR84 GLRQLTDAYE94 CLDASRPWLC104 YWILHSLELL114 DEPIPQIVAT 124 DVCQFLELCQ134 SPEGGFGGGP144 GQYPHLAPTY154 AAVNALCIIG164 TEEAYDIINR 174 EKLLQYLYSL184 KQPDGSFLMH194 VGGEVDVRSA204 YCAASVASLT214 NIITPDLFEG 224 TAEWIARCQN234 WEGGIGGVPG244 MEAHGGYTFC254 GLAALVILKR264 ERSLNLKSLL 274 QWVTSRQMRF284 EGGFQGRCNK294 LVDGCYSFWQ304 AGLLPLLHRA314 LHAQGDPALS 324 MSHWMFHQQA334 LQEYILMCCQ344 CPAGGLLDKP354 GKSRDFYHTC364 YCLSGLSIAQ 374 HFGSGAMLHD384 VVLGVPENAL394 QPTHPVYNIG404 PDKVIQATTY414 FLQKPVPGFE 424
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| Ligand Name: L-778123 | Ligand Info | |||||
| Structure Description | Human protein farnesyltransferase complexed with L-778,123 and FPP | PDB:1S63 | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [33] |
| PDB Sequence |
SSPVWSEPLY
24 SLRPEHARER34 LQDDSVETVT44 SIEQAKVEEK54 IQEVFSSYKF64 NHLVPRLVLQ 74 REKHFHYLKR84 GLRQLTDAYE94 CLDASRPWLC104 YWILHSLELL114 DEPIPQIVAT 124 DVCQFLELCQ134 SPEGGFGGGP144 GQYPHLAPTY154 AAVNALCIIG164 TEEAYDIINR 174 EKLLQYLYSL184 KQPDGSFLMH194 VGGEVDVRSA204 YCAASVASLT214 NIITPDLFEG 224 TAEWIARCQN234 WEGGIGGVPG244 MEAHGGYTFC254 GLAALVILKR264 ERSLNLKSLL 274 QWVTSRQMRF284 EGGFQGRCNK294 LVDGCYSFWQ304 AGLLPLLHRA314 LHAQGDPALS 324 MSHWMFHQQA334 LQEYILMCCQ344 CPAGGLLDKP354 GKSRDFYHTC364 YCLSGLSIAQ 374 HFGSGAMLHD384 VVLGVPENAL394 QPTHPVYNIG404 PDKVIQATTY414 FLQKPVPGFE 424
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| 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).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
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
Human Pathway Affiliation
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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Terpenoid backbone biosynthesis | hsa00900 | Affiliated Target |
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| Class: Metabolism => Metabolism of terpenoids and polyketides | Pathway Hierarchy | ||
| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 3.26E-04 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 5.00E-01 |
| Neighborhood connectivity | 2.70E+01 | Topological coefficient | 2.25E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Terpenoid backbone biosynthesis | |||||
| 2 | Biosynthesis of antibiotics | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TSH Signaling Pathway | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Inactivation, recovery and regulation of the phototransduction cascade | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Visual phototransduction | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | US patent application no. 2005,0227,929, Combination therapy comprising a cox-2 inhibitor and an antineoplastic agent. | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019239) | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014561) | |||||
| REF 4 | Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res. 1995 Nov 15;55(22):5310-4. | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004903) | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004901) | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013446) | |||||
| REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002714) | |||||
| REF 9 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004259) | |||||
| REF 10 | 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 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012642) | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005580) | |||||
| REF 13 | XR3054, structurally related to limonene, is a novel inhibitor of farnesyl protein transferase. Eur J Cancer. 1999 Jun;35(6):1014-9. | |||||
| REF 14 | Potent farnesyltransferase inhibitor ABT-100 abrogates acute allograft rejection. J Heart Lung Transplant. 2005 Sep;24(9):1403-9. | |||||
| REF 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. | |||||
| REF 16 | WO patent application no. 2011,0881,26, Treatment of viral infection with prenyltransferase inhibitors. | |||||
| REF 17 | 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. | |||||
| REF 18 | Ras farnesyltransferase: a new therapeutic target. J Med Chem. 1997 Sep 12;40(19):2971-90. | |||||
| REF 19 | A novel metal-chelating inhibitor of protein farnesyltransferase. Bioorg Med Chem Lett. 2003 May 5;13(9):1523-6. | |||||
| REF 20 | Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase. J Med Chem. 1997 Jun 6;40(12):1763-7. | |||||
| REF 21 | Exploring the role of bromine at C(10) of (+)-4-[2-[4-(8-chloro-3,10-dibromo- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2- oxoethyl]-1-piperidinecarboxamide (Sch-66336): the discovery of indolocycloheptapyridine inhibitors of farnesyl protein transferase. J Med Chem. 2002 Aug 29;45(18):3854-64. | |||||
| REF 22 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 23 | Design, synthesis, and structure-activity relationships of tetrahydroquinoline-based farnesyltransferase inhibitors. Bioorg Med Chem Lett. 2005 Apr 1;15(7):1895-9. | |||||
| REF 24 | Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. J Med Chem. 2005 Jun 2;48(11):3704-13. | |||||
| REF 25 | Clavaric acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase. J Med Chem. 1998 Nov 5;41(23):4492-501. | |||||
| REF 26 | Recent progress in protein farnesyltransferase inhibition. IDrugs. 2000 Nov;3(11):1336-45. | |||||
| REF 27 | Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem. 1995 Nov 10;270(45):26802-6. | |||||
| REF 28 | Improvement of biological activity and proteolytic stability of peptides by coupling with a cyclic peptide. Bioorg Med Chem Lett. 2003 Aug 4;13(15):2583-6. | |||||
| REF 29 | A novel class of highly potent, selective, and non-peptidic inhibitor of Ras farnesyltransferase (FTase). Bioorg Med Chem Lett. 2001 Dec 3;11(23):3069-72. | |||||
| REF 30 | Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. J Med Chem. 1997 Jan 17;40(2):192-200. | |||||
| REF 31 | Synthesis and evaluation of benzophenone-based photoaffinity labeling analogs of prenyl pyrophosphates containing stable amide linkages, Bioorg. Med. Chem. Lett. 7(16):2125-2130 (1997). | |||||
| REF 32 | Crystal structures of the anticancer clinical candidates R115777 (Tipifarnib) and BMS-214662 complexed with protein farnesyltransferase suggest a mechanism of FTI selectivity. Biochemistry. 2004 Jun 8;43(22):6877-84. | |||||
| REF 33 | Crystallographic analysis reveals that anticancer clinical candidate L-778,123 inhibits protein farnesyltransferase and geranylgeranyltransferase-I by different binding modes. Biochemistry. 2004 Jul 20;43(28):9000-8. | |||||
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