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cyclin dependent kinase 8

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Target not currently curated in GtoImmuPdb

Target id: 1980

Nomenclature: cyclin dependent kinase 8

Abbreviated Name: CDK8

Family: CDK8 subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 464 13q12.13 CDK8 cyclin dependent kinase 8
Mouse - 464 5 G3 Cdk8 cyclin dependent kinase 8
Previous and Unofficial Names Click here for help
Cell division protein kinase 8 | Mediator of RNA polymerase II transcription subunit CDK8 | cyclin-dependent kinase 8
Database Links Click here for help
Alphafold P49336 (Hs), Q8R3L8 (Mm)
BRENDA 2.7.11.22, 2.7.11.23
ChEMBL Target CHEMBL5719 (Hs), CHEMBL4296068 (Mm)
Ensembl Gene ENSG00000132964 (Hs), ENSMUSG00000029635 (Mm)
Entrez Gene 1024 (Hs), 264064 (Mm)
Human Protein Atlas ENSG00000132964 (Hs)
KEGG Enzyme 2.7.11.22, 2.7.11.23
KEGG Gene hsa:1024 (Hs), mmu:264064 (Mm)
OMIM 603184 (Hs)
Pharos P49336 (Hs)
RefSeq Nucleotide NM_001260 (Hs), NM_153599 (Mm)
RefSeq Protein NP_001251 (Hs), NP_705827 (Mm)
UniProtKB P49336 (Hs), Q8R3L8 (Mm)
Wikipedia CDK8 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of human CDK8/CycC
PDB Id:  3RGF
Resolution:  2.2Å
Species:  Human
References:  12
Image of receptor 3D structure from RCSB PDB
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 Id:  5BNJ
Ligand:  CCT251545
Resolution:  2.64Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human CDK8-Cyclin C in complex with cortistatin A.
PDB Id:  4CRL
Ligand:  cortistatin A
Resolution:  2.4Å
Species:  Human
References:  9
Enzyme Reaction Click here for help
EC Number: 2.7.11.22
EC Number: 2.7.11.23

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CCT251545 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.4 pKd 3
⤷ pKd 8.4 (Kd 3.8x10-9 M) [3]
Description: CDK8/cyclin C.
ponatinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.2 pKd 3
⤷ pKd 8.2 (Kd 6.77x10-9 M) [3]
Description: CDK8/cyclin C.
linifanib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.2 pKd 3
⤷ pKd 8.2 (Kd 6.84x10-9 M) [3]
Description: CDK8/cyclin C.
cortistatin A Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 pKd 2
⤷ pKd 7.8 (Kd 1.7x10-8 M) [2]
sorafenib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.0 pKd 3
⤷ pKd 7.0 (Kd 9.96x10-8 M) [3]
Description: CDK8/cyclin C.
compound 51 [Mallinger et al., 2016] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.3 pIC50 7
⤷ pIC50 8.3 (IC50 5.1x10-9 M) [7]
voruciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.9 pIC50 8
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [8]
Description: Inhibition of CDK8/cyclinC.
JH-VIII-49 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pIC50 5
⤷ pIC50 7.8 (IC50 1.6x10-8 M) [5]
compound 20 [Bergeron et al., 2016] Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.8 pIC50 1
⤷ pIC50 7.8 (IC50 1.74x10-8 M) [1]
DS96432529 Small molecule or natural product Hs Inhibition 7.5 pIC50 11
⤷ pIC50 7.5 (IC50 3.3x10-8 M) [11]
Description: Measured in a NanoBRET assay in HEK293 cells expressing CDK8/Cyclin C
JH-XI-10-02 Small molecule or natural product Hs Inhibition 6.8 pIC50 5
⤷ pIC50 6.8 (IC50 1.59x10-7 M) [5]
CDK12 inhibitor 2 Small molecule or natural product Click here for species-specific activity table Hs Inhibition <5.0 pIC50 6
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [6]
compound 1 [PMID: 24793884] Small molecule or natural product Click here for species-specific activity table Hs Inhibition - - 10
⤷ [10]
Description: Measured as % inhibition using 1μM compound.
Inhibitor Comments
CDK8 activity is inhibited by approximately 88% (average of n=2) in the presence of 1μM compound 1 [PMID 24793884] [10].
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 4,13
Key to terms and symbols Click column headers to sort
Target used in screen: CDK8
Ligand Sp. Type Action Value Parameter
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 8.9 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition 7.0 pKd
alvocidib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 pKd
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
sorafenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
BMS-387032 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.9 pKd
PLX-4720 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.7 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Cellular signalling

References

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1. Bergeron P, Koehler MF, Blackwood EM, Bowman K, Clark K, Firestein R, Kiefer JR, Maskos K, McCleland ML, Orren L et al.. (2016) Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8. ACS Med Chem Lett, 7 (6): 595-600. [PMID:27326333]

2. Cee VJ, Chen DY, Lee MR, Nicolaou KC. (2009) Cortistatin A is a high-affinity ligand of protein kinases ROCK, CDK8, and CDK11. Angew Chem Int Ed Engl, 48 (47): 8952-7. [PMID:19844931]

3. Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz MJ, Mallinger A, Samant RS, Czodrowski P, Musil D et al.. (2015) A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol, 11 (12): 973-80. [PMID:26502155]

4. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

5. Hatcher JM, Wang ES, Johannessen L, Kwiatkowski N, Sim T, Gray NS. (2018) Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8. ACS Med Chem Lett, 9 (6): 540-545. [PMID:29937979]

6. Ito M, Tanaka T, Toita A, Uchiyama N, Kokubo H, Morishita N, Klein MG, Zou H, Murakami M, Kondo M et al.. (2018) Discovery of 3-Benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors. J Med Chem, 61 (17): 7710-7728. [PMID:30067358]

7. Mallinger A, Schiemann K, Rink C, Sejberg J, Honey MA, Czodrowski P, Stubbs M, Poeschke O, Busch M, Schneider R et al.. (2016) 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. ACS Med Chem Lett, 7 (6): 573-8. [PMID:27326329]

8. Paiva C, Godbersen JC, Soderquist RS, Rowland T, Kilmarx S, Spurgeon SE, Brown JR, Srinivasa SP, Danilov AV. (2015) Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells. PLoS ONE, 10 (11): e0143685. [PMID:26606677]

9. Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, Caruso BT, Arefolov A, Fadeyi O, Christie AL et al.. (2015) Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature, 526 (7572): 273-276. [PMID:26416749]

10. Reichelt A, Bailis JM, Bartberger MD, Yao G, Shu H, Kaller MR, Allen JG, Weidner MF, Keegan KS, Dao JH. (2014) Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors. Eur J Med Chem, 80: 364-82. [PMID:24793884]

11. Saito K, Shinozuka T, Nakao A, Kunikata T, Nakai D, Nagai Y, Naito S. (2021) Discovery of 3-amino-4-{(3S)-3-[(2-ethoxyethoxy)methyl]piperidin-1-yl}thieno[2,3-b]pyridine-2-carboxamide (DS96432529): A potent and orally active bone anabolic agent. Bioorg Med Chem Lett, 54: 128440. [PMID:34742889]

12. Schneider EV, Böttcher J, Blaesse M, Neumann L, Huber R, Maskos K. (2011) The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder. J Mol Biol, 412 (2): 251-66. [PMID:21806996]

13. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

How to cite this page

CDK8 subfamily: cyclin dependent kinase 8. Last modified on 13/01/2022. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1980.