cyclin dependent kinase 8 | CDK8 subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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cyclin dependent kinase 8

Target not currently curated in GtoImmuPdb

Target id: 1980

Nomenclature: cyclin dependent kinase 8

Abbreviated Name: CDK8

Family: CDK8 subfamily

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 464 13q12 CDK8 cyclin dependent kinase 8
Mouse - 464 5 G3 Cdk8 cyclin-dependent kinase 8
Previous and Unofficial Names
Cell division protein kinase 8 | Mediator of RNA polymerase II transcription subunit CDK8 | cyclin-dependent kinase 8
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of human CDK8/CycC
PDB Id:  3RGF
Resolution:  2.2Å
Species:  Human
References:  11
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
EC Number: 2.7.11.22
EC Number: 2.7.11.23

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CCT251545 Hs Inhibition 8.4 pKd 3
pKd 8.4 (Kd 3.8x10-9 M) [3]
Description: CDK8/cyclin C.
ponatinib Hs Inhibition 8.2 pKd 3
pKd 8.2 (Kd 6.77x10-9 M) [3]
Description: CDK8/cyclin C.
linifanib Hs Inhibition 8.2 pKd 3
pKd 8.2 (Kd 6.84x10-9 M) [3]
Description: CDK8/cyclin C.
cortistatin A Hs Inhibition 7.8 pKd 2
pKd 7.8 (Kd 1.7x10-8 M) [2]
sorafenib 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] Hs Inhibition 8.3 pIC50 7
pIC50 8.3 (IC50 5.1x10-9 M) [7]
voruciclib Hs Inhibition 7.9 pIC50 8
pIC50 7.9 (IC50 1.2x10-8 M) [8]
Description: Inhibition of CDK8/cyclinC.
JH-VIII-49 Hs Inhibition 7.8 pIC50 5
pIC50 7.8 (IC50 1.6x10-8 M) [5]
compound 20 [Bergeron et al., 2016] Hs Inhibition 7.8 pIC50 1
pIC50 7.8 (IC50 1.74x10-8 M) [1]
JH-XI-10-02 Hs Inhibition 6.8 pIC50 5
pIC50 6.8 (IC50 1.59x10-7 M) [5]
CDK12 inhibitor 2 Hs Inhibition <5.0 pIC50 6
pIC50 <5.0 (IC50 >1x10-5 M) [6]
compound 1 [PMID: 24793884] 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
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: 4,12

Key to terms and symbols Click column headers to sort
Target used in screen: CDK8
Ligand Sp. Type Action Value Parameter
AST-487 Hs Inhibitor Inhibition 8.9 pKd
linifanib Hs Inhibitor Inhibition 7.0 pKd
alvocidib Hs Inhibitor Inhibition 6.9 pKd
foretinib Hs Inhibitor Inhibition 6.9 pKd
doramapimod Hs Inhibitor Inhibition 6.7 pKd
sorafenib Hs Inhibitor Inhibition 6.5 pKd
staurosporine Hs Inhibitor Inhibition 6.3 pKd
BMS-387032 Hs Inhibitor Inhibition 5.9 pKd
PLX-4720 Hs Inhibitor Inhibition 5.7 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »

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. 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]

12. 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 28/08/2018. Accessed on 15/09/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1980.