Target Information
| Target General Information | Top | |||||
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| Target ID |
T58470
(Former ID: TTDR00224)
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| Target Name |
Cyclin A2 (CCNA2)
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| Synonyms |
Cyclin-A2; Cyclin-A; Cyclin A; CCNA
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| Gene Name |
CCNA2
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Retina cancer [ICD-11: 2D02] | |||||
| Function |
Functions through the formation of specific serine/threonine protein kinase holoenzyme complexes with the cyclin-dependent protein kinases CDK1 or CDK2. The cyclin subunit confers the substrate specificity of these complexes and differentially interacts with and activates CDK1 and CDK2 throughout the cell cycle. Cyclin which controls both the G1/S and the G2/M transition phases of the cell cycle.
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| UniProt ID | ||||||
| Sequence |
MLGNSAPGPATREAGSALLALQQTALQEDQENINPEKAAPVQQPRTRAALAVLKSGNPRG
LAQQQRPKTRRVAPLKDLPVNDEHVTVPPWKANSKQPAFTIHVDEAEKEAQKKPAESQKI EREDALAFNSAISLPGPRKPLVPLDYPMDGSFESPHTMDMSIILEDEKPVSVNEVPDYHE DIHTYLREMEVKCKPKVGYMKKQPDITNSMRAILVDWLVEVGEEYKLQNETLHLAVNYID RFLSSMSVLRGKLQLVGTAAMLLASKFEEIYPPEVAEFVYITDDTYTKKQVLRMEHLVLK VLTFDLAAPTVNQFLTQYFLHQQPANCKVESLAMFLGELSLIDADPYLKYLPSVIAGAAF HLALYTVTGQSWPESLIRKTGYTLESLKPCLMDLHQTYLKAPQHAQQSIREKYKNSKYHG VSLLNPPETLNL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T86UXL | |||||
| Drugs and Modes of Action | Top | |||||
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| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | PD-0183812 | Drug Info | Terminated | Retinoblastoma | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 23 Inhibitor drugs | + | ||||
| 1 | PD-0183812 | Drug Info | [1] | |||
| 2 | 2,5-dichloro-N-p-tolylthiophene-3-sulfonamide | Drug Info | [3] | |||
| 3 | 3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol | Drug Info | [4] | |||
| 4 | 4-(phenyldiazenyl)-1H-pyrazole-3,5-diamine | Drug Info | [4] | |||
| 5 | 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol | Drug Info | [4] | |||
| 6 | 6-(3-Amino-benzyloxy)-9H-purin-2-ylamine | Drug Info | [5] | |||
| 7 | 6-(3-Methyl-benzyloxy)-9H-purin-2-ylamine | Drug Info | [5] | |||
| 8 | 6-(Cyclohex-3-enylmethoxy)-9H-purin-2-ylamine | Drug Info | [5] | |||
| 9 | 6-Cyclohexylmethoxy-pyrimidine-2,4,5-triamine | Drug Info | [6] | |||
| 10 | 6-O-Cyclohexylmethyl Guanine | Drug Info | [7] | |||
| 11 | aloisine A | Drug Info | [8] | |||
| 12 | GW-8510 | Drug Info | [9] | |||
| 13 | MERIOLIN 1 | Drug Info | [10] | |||
| 14 | MERIOLIN 2 | Drug Info | [10] | |||
| 15 | MERIOLIN 3 | Drug Info | [10] | |||
| 16 | MERIOLIN 4 | Drug Info | [10] | |||
| 17 | MERIOLIN 5 | Drug Info | [10] | |||
| 18 | MERIOLIN 6 | Drug Info | [10] | |||
| 19 | MERIOLIN 7 | Drug Info | [10] | |||
| 20 | MERIOLIN 8 | Drug Info | [10] | |||
| 21 | NU-6027 | Drug Info | [6] | |||
| 22 | Purvalanol A | Drug Info | [11] | |||
| 23 | RESCOVITINE | Drug Info | [12] | |||
| 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: Alpha-Aminobutyric Acid | Ligand Info | |||||
| Structure Description | Differential Binding Of Inhibitors To Active And Inactive Cdk2 Provides Insights For Drug Design | PDB:2C5V | ||||
| Method | X-ray diffraction | Resolution | 2.90 Å | Mutation | No | [13] |
| PDB Sequence |
VPDYHEDIHT
184 YLREMEVKCK194 PKVGYMKKQP204 DITNSMRAIL214 VDWLVEVGEE224 YKLQNETLHL 234 AVNYIDRFLS244 SMSVLRGKLQ254 LVGTAAMLLA264 SKFEEIYPPE274 VAEFVYITDD 284 TYTKKQVLRM294 EHLVLKVLTF304 DLAAPTVNQF314 LTQYFLHQQP324 ANCKVESLAM 334 FLGELSLIDA344 DPYLKYLPSV354 IAGAAFHLAL364 YTVTGQSWPE374 SLIRKTGYTL 384 ESLKPCLMDL394 HQTYLKAPQH404 AQQSIREKYK414 NSKYHGVSLL424 NPPETLNL |
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| Ligand Name: Phosphonothreonine | Ligand Info | |||||
| Structure Description | Thr 160 phosphorylated CDK2 H84S, Q85M, K89D - human cyclin A3 complex with ATP | PDB:4EOJ | ||||
| Method | X-ray diffraction | Resolution | 1.65 Å | Mutation | Yes | [14] |
| PDB Sequence |
PDYHEDIHTY
185 LREMEVKCKP195 KVGYMKKQPD205 ITNSMRAILV215 DWLVEVGEEY225 KLQNETLHLA 235 VNYIDRFLSS245 MSVLRGKLQL255 VGTAAMLLAS265 KFEEIYPPEV275 AEFVYITDDT 285 YTKKQVLRME295 HLVLKVLTFD305 LAAPTVNQFL315 TQYFLHQQPA325 NCKVESLAMF 335 LGELSLIDAD345 PYLKYLPSVI355 AGAAFHLALY365 TVTGQSWPES375 LIRKTGYTLE 385 SLKPCLMDLH395 QTYLKAPQHA405 QQSIREKYKN415 SKYHGVSLLN425 PPETLNL |
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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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| Cell cycle | hsa04110 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| AMPK signaling pathway | hsa04152 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Cellular senescence | hsa04218 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Progesterone-mediated oocyte maturation | hsa04914 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 93 | Degree centrality | 9.99E-03 | Betweenness centrality | 3.21E-03 |
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| Closeness centrality | 2.51E-01 | Radiality | 1.44E+01 | Clustering coefficient | 2.16E-01 |
| Neighborhood connectivity | 4.03E+01 | Topological coefficient | 4.75E-02 | Eccentricity | 12 |
| 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 Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem. 2000 Nov 30;43(24):4606-16. | |||||
| 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 800014130) | |||||
| REF 3 | Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases, Bioorg. Med. Chem. Lett. 20(13):3863-3867 (2010). | |||||
| REF 4 | 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006 Nov 2;49(22):6500-9. | |||||
| REF 5 | Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives. J Med Chem. 2002 Aug 1;45(16):3381-93. | |||||
| REF 6 | 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2. Bioorg Med Chem Lett. 2003 Jan 20;13(2):217-22. | |||||
| REF 7 | N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2. J Med Chem. 2004 Jul 15;47(15):3710-22. | |||||
| REF 8 | Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects. J Med Chem. 2003 Jan 16;46(2):222-36. | |||||
| REF 9 | Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7. | |||||
| REF 10 | Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin com... J Med Chem. 2008 Feb 28;51(4):737-51. | |||||
| REF 11 | The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315. | |||||
| REF 12 | Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors. Eur J Med Chem. 2010 Mar;45(3):1158-66. | |||||
| REF 13 | Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design. Chem Biol. 2006 Feb;13(2):201-11. | |||||
| REF 14 | An integrated chemical biology approach provides insight into Cdk2 functional redundancy and inhibitor sensitivity. Chem Biol. 2012 Aug 24;19(8):1028-40. | |||||
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