Target Information
| Target General Information | Top | |||||
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| Target ID |
T23787
(Former ID: TTDI02065)
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| Target Name |
Renal carcinoma antigen NY-REN-56 (PFKFB3)
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| Synonyms |
iPFK2; Renal carcinoma antigen NYREN56; PFKFB3; Fructose2,6bisphosphatase; 6phosphofructo2kinase/fructose2,6bisphosphatase 3; 6PF2K/Fru2,6P2ase brain/placentatype isozyme; 6PF2K/Fru2,6P2ase 3
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| Gene Name |
PFKFB3
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Synthesis and degradation of fructose 2,6-bisphosphate.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| Sequence |
MPLELTQSRVQKIWVPVDHRPSLPRSCGPKLTNSPTVIVMVGLPARGKTYISKKLTRYLN
WIGVPTKVFNVGEYRREAVKQYSSYNFFRPDNEEAMKVRKQCALAALRDVKSYLAKEGGQ IAVFDATNTTRERRHMILHFAKENDFKAFFIESVCDDPTVVASNIMEVKISSPDYKDCNS AEAMDDFMKRISCYEASYQPLDPDKCDRDLSLIKVIDVGRRFLVNRVQDHIQSRIVYYLM NIHVQPRTIYLCRHGENEHNLQGRIGGDSGLSSRGKKFASALSKFVEEQNLKDLRVWTSQ LKSTIQTAEALRLPYEQWKALNEIDAGVCEELTYEEIRDTYPEEYALREQDKYYYRYPTG ESYQDLVQRLEPVIMELERQENVLVICHQAVLRCLLAYFLDKSAEEMPYLKCPLHTVLKL TPVAYGCRVESIYLNVESVCTHRERSEDAKKGPNPLMRRNSVTPLASPEPTKKPRINSFE EHVASTSAALPSCLPPEVPTQLPGQNMKGSRSSADSSRKH Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T58TFI | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | PFK-158 | Drug Info | Phase 1 | Solid tumour/cancer | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | PFK-158 | Drug Info | [1] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | 3PO | Drug Info | [3] | |||
| 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: Glutathione | Ligand Info | |||||
| Structure Description | S-glutathionylated PFKFB3 | PDB:4MA4 | ||||
| Method | X-ray diffraction | Resolution | 2.23 Å | Mutation | No | [4] |
| PDB Sequence |
LELTQSRVQK
11 IWVPVDHRPS21 LPNSPTVIVM39 VGLPARGKTY49 ISKKLTRYLN59 WIGVPTKVFN 69 VGEYRREAVK79 QYSSYNFFRP89 DNEEAMKVRK99 QCALAALRDV109 KSYLAKEGGQ 119 IAVFDATNTT129 RERRHMILHF139 AKENDFKAFF149 IESVCDDPTV159 VASNIMEVKI 169 SSPDYKDCNS179 AEAMDDFMKR189 ISCYEASYQP199 LDPDKCDRDL209 SLIKVIDVGR 219 RFLVNRVQDH229 IQSRIVYYLM239 NIHVQPRTIY249 LCRHGENEHN259 LQGRIGGDSG 269 LSSRGKKFAS279 ALSKFVEEQN289 LKDLRVWTSQ299 LKSTIQTAEA309 LRLPYEQWKA 319 LNEIDAGVCE329 ELTYEEIRDT339 YPEEYALREQ349 DKYYYRYPTG359 ESYQDLVQRL 369 EPVIMELERQ379 ENVLVICHQA389 VLRCLLAYFL399 DKSAEEMPYL409 KCPLHTVLKL 419 TPVAYGCRVE429 SIYLNVESVC439 THRERSNPLM456 RRNS
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| Ligand Name: Pyrophosphate 2- | Ligand Info | |||||
| Structure Description | Human PFKFB3 in complex with a N-Aryl 6-Aminoquinoxaline inhibitor 2 | PDB:6HVI | ||||
| Method | X-ray diffraction | Resolution | 1.96 Å | Mutation | No | [5] |
| PDB Sequence |
PLELTQSRVQ
10 KIWVPVHRNS33 PTVIVMVGLP43 ARGKTYISKK53 LTRYLNWIGV63 PTKVFNVGEY 73 RREAVKQYSS83 YNFFRPDNEE93 AMKVRKQCAL103 AALRDVKSYL113 AKEGGQIAVF 123 DATNTTRERR133 HMILHFAKEN143 DFKAFFIESV153 CDDPTVVASN163 IMEVKISSPD 173 YKDCNSAEAM183 DDFMKRISCY193 EASYQPLDPD203 KCDRDLSLIK213 VIDVGRRFLV 223 NRVQDHIQSR233 IVYYLMNIHV243 QPRTIYLCRH253 GENEHNLQGR263 IGGDSGLSSR 273 GKKFASALSK283 FVEEQNLKDL293 RVWTSQLKST303 IQTAEALRLP313 YEQWKALNEI 323 DAGVCEELTY333 EEIRDTYPEE343 YALREQDKYY353 YRYPTGESYQ363 DLVQRLEPVI 373 MELERQENVL383 VICHQAVLRC393 LLAYFLDKSA403 EEMPYLKCPL413 HTVLKLTPVA 423 YGCRVESIYL433 NVESVCTHRE443 RSE
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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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| Fructose and mannose metabolism | hsa00051 | Affiliated Target |
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| Class: Metabolism => Carbohydrate metabolism | Pathway Hierarchy | ||
| HIF-1 signaling pathway | hsa04066 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| AMPK signaling pathway | hsa04152 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 1.85E-05 |
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| Closeness centrality | 1.89E-01 | Radiality | 1.32E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 5.00E+00 | Topological coefficient | 3.17E-01 | 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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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 1 BioCyc Pathways | + | ||||
| 1 | Fructose 2,6-bisphosphate synthesis | |||||
| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Fructose and mannose metabolism | |||||
| 2 | HIF-1 signaling pathway | |||||
| 3 | AMPK signaling pathway | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | HIF-1-alpha transcription factor network | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Glycolysis | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Metabolism of carbohydrates | |||||
| 2 | AMPK Signaling | |||||
| References | Top | |||||
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| REF 1 | Discovery of a PFKFB3 inhibitor for phase I trial testing that synergizes with the B-Raf inhibitor vemurafenib. Cancer Metab. 2014; 2(Suppl 1): P14. | |||||
| REF 2 | ClinicalTrials.gov (NCT02044861) Phase 1 Safety Study of ACT-PFK-158, 2HCl in Patients With Advanced Solid Malignancies. U.S. National Institutes of Health. | |||||
| REF 3 | CPEB4 Increases Expression of PFKFB3 to Induce Glycolysis and Activate Mouse and Human Hepatic Stellate Cells, Promoting Liver Fibrosis. Gastroenterology. 2020 Jul;159(1):273-288. | |||||
| REF 4 | PFKFB3 regulates oxidative stress homeostasis via its S-glutathionylation in cancer. J Mol Biol. 2014 Feb 20;426(4):830-42. | |||||
| REF 5 | Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors. ChemMedChem. 2019 Jan 8;14(1):169-181. | |||||
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