Target Information
| Target General Information | Top | |||||
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| Target ID |
T10822
(Former ID: TTDR00298)
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| Target Name |
Cyclin-dependent kinase 8 (CDK8)
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| Synonyms |
Protein kinase K35; Mediator of RNA polymerase II transcription subunit CDK8; Mediator complex subunit CDK8; Cell division protein kinase 8
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| Gene Name |
CDK8
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| Function |
Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.22
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| Sequence |
MDYDFKVKLSSERERVEDLFEYEGCKVGRGTYGHVYKAKRKDGKDDKDYALKQIEGTGIS
MSACREIALLRELKHPNVISLQKVFLSHADRKVWLLFDYAEHDLWHIIKFHRASKANKKP VQLPRGMVKSLLYQILDGIHYLHANWVLHRDLKPANILVMGEGPERGRVKIADMGFARLF NSPLKPLADLDPVVVTFWYRAPELLLGARHYTKAIDIWAIGCIFAELLTSEPIFHCRQED IKTSNPYHHDQLDRIFNVMGFPADKDWEDIKKMPEHSTLMKDFRRNTYTNCSLIKYMEKH KVKPDSKAFHLLQKLLTMDPIKRITSEQAMQDPYFLEDPLPTSDVFAGCQIPYPKREFLT EEEPDDKGDKKNQQQQQGNNHTNGTGHPGNQDSSHTQGPPLKKVRVVPPTTTSGGLIMTS DYQRSNPHAAYPNPGPSTSQPQSSMGYSATSQQPPQYSHQTHRY 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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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | SEL120 | Drug Info | Phase 1 | Acute myeloid leukaemia | [2] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | CCT251545 | Drug Info | Preclinical | Colorectal cancer | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 6 Inhibitor drugs | + | ||||
| 1 | SEL120 | Drug Info | [4] | |||
| 2 | Macrocycle derivative 14 | Drug Info | [1] | |||
| 3 | Tricyclic benzimidazole derivative 1 | Drug Info | [1] | |||
| 4 | CCT251545 | Drug Info | [3] | |||
| 5 | Oxindole 16 (compound 3) | Drug Info | [5] | |||
| 6 | Oxindole 94 | Drug Info | [5] | |||
| 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: Sorafenib | Ligand Info | |||||
| Structure Description | Crystal Structure of human CDK8/CycC | PDB:3RGF | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [6] |
| PDB Sequence |
DKMDYDFKVK
8 LSSERERVED18 LFEYEGCKVG33 HVYKAKRKDG43 KDDKDYALKQ53 IEGTGISMSA 63 CREIALLREL73 KHPNVISLQK83 VFLSHADRKV93 WLLFDYAEHD103 LWHIIKFHRA 113 SKLPRGMVKS130 LLYQILDGIH140 YLHANWVLHR150 DLKPANILVM160 GEGPERGRVK 170 IADMGFARVT196 FWYRAPELLL206 GARHYTKAID216 IWAIGCIFAE226 LLTSEPIFHC 236 RQNPYHHDQL252 DRIFNVMGFP262 ADKDWEDIKK272 MPEHSTLMKD282 FRRNTYTNCS 292 LIKYMEKHKV302 KPDSKAFHLL312 QKLLTMDPIK322 RITSEQAMQD332 PYFLEDPLPT 342 SDVFAGCQIP352 Y
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VAL35
3.812
ALA50
3.335
LYS52
3.562
GLU66
2.761
LEU69
4.276
LEU70
3.682
LEU73
3.612
VAL78
3.459
ILE79
3.514
LEU95
4.871
PHE97
3.496
ASP98
3.555
TYR99
3.548
ALA100
2.647
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| Ligand Name: CCT251545 | Ligand Info | |||||
| Structure Description | CDK8/CYCC IN COMPLEX WITH 8-{3-Chloro-5-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyridin- 4-yl}-2,8-diaza-spiro[4.5]decan-1-one | PDB:5BNJ | ||||
| Method | X-ray diffraction | Resolution | 2.64 Å | Mutation | No | [7] |
| PDB Sequence |
DKMDYDFKVK
8 LSSERERVED18 LFEYEGCKVG28 RGTYGHVYKA38 KRKDGKDDKD48 YALKQIEGTG 58 ISMSACREIA68 LLRELKHPNV78 ISLQKVFLSH88 ADRKVWLLFD98 YAEHDLWHII 108 KFHRASKANQ122 LPRGMVKSLL132 YQILDGIHYL142 HANWVLHRDL152 KPANILVMGE 162 GPERGRVKIA172 DMGFARLFNS182 PLTFWYRAPE203 LLLGARHYTK213 AIDIWAIGCI 223 FAELLTSEPI233 FHCRQNPYHH249 DQLDRIFNVM259 GFPADKDWED269 IKKMPEHSTL 279 MKDFRRNTYT289 NCSLIKYMEK299 HKVKPDSKAF309 HLLQKLLTMD319 PIKRITSEQA 329 MQDPYFLEDP339 LPTSDVFAGC349 QIPYPKREFL359 TEE
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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).
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
Biological Network Descriptors
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| Degree | 35 | Degree centrality | 3.76E-03 | Betweenness centrality | 3.58E-04 |
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| Closeness centrality | 2.16E-01 | Radiality | 1.38E+01 | Clustering coefficient | 7.24E-01 |
| Neighborhood connectivity | 3.23E+01 | Topological coefficient | 1.54E-01 | Eccentricity | 11 |
| 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-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70. | |||||
| REF 2 | ClinicalTrials.gov (NCT04021368) SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome. U.S. National Institutes of Health. | |||||
| REF 3 | Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018 May;17(5):353-377. | |||||
| REF 4 | Clinical pipeline report, company report or official report of Ryvu Therapeutics. | |||||
| REF 5 | Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci. 2002 Sep;23(9):417-25. | |||||
| REF 6 | The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder. J Mol Biol. 2011 Sep 16;412(2):251-66. | |||||
| REF 7 | A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol. 2015 Dec;11(12):973-980. | |||||
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