cyclin dependent kinase 9 | CDK9 subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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cyclin dependent kinase 9

Target not currently curated in GtoImmuPdb

Target id: 1981

Nomenclature: cyclin dependent kinase 9

Abbreviated Name: CDK9

Family: CDK9 subfamily

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 372 9q34.1 CDK9 cyclin dependent kinase 9
Mouse - 372 2 B Cdk9 cyclin-dependent kinase 9 (CDC2-related kinase)
Rat - 372 3 p11 Cdk9 cyclin-dependent kinase 9
Previous and Unofficial Names
CDC2L4 | cell division protein kinase 9 | TAK
Database Links
BRENDA 2.7.11.22, 2.7.11.23
ChEMBL Target CHEMBL3116 (Hs), CHEMBL4105875 (Mm)
Ensembl Gene ENSG00000136807 (Hs), ENSMUSG00000009555 (Mm), ENSRNOG00000022586 (Rn)
Entrez Gene 1025 (Hs), 107951 (Mm), 362110 (Rn)
Human Protein Atlas ENSG00000136807 (Hs)
KEGG Enzyme 2.7.11.22, 2.7.11.23
KEGG Gene hsa:1025 (Hs), mmu:107951 (Mm), rno:362110 (Rn)
OMIM 603251 (Hs)
Pharos P50750 (Hs)
RefSeq Nucleotide NM_001261 (Hs), NM_130860 (Mm), NM_001007743 (Rn)
RefSeq Protein NP_001252 (Hs), NP_570930 (Mm), NP_001007744 (Rn)
UniProtKB P50750 (Hs), Q99J95 (Mm), Q641Z4 (Rn)
Wikipedia CDK9 (Hs)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Human CDK9/cyclinT1
PDB Id:  3BLH
Resolution:  2.48Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Human CDK9/cyclinT1 in complex with Flavopiridol
PDB Id:  3BLR
Resolution:  2.8Å
Species:  Human
References:  3
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
BMS-387032 Hs Inhibition 8.4 pKi 12
⤷ pKi 8.4 (Ki 4x10-9 M) [12]
seliciclib Hs Inhibition 6.1 pKi 12
⤷ pKi 6.1 (Ki 7.9x10-7 M) [12]
Description: CDK9/cyclin T complex used in assay
NVP-2 Hs Inhibition 9.3 pIC50 2
⤷ pIC50 9.3 (IC50 5x10-10 M) [2]
RGB-286638 Hs Inhibition 9.0 pIC50 6
⤷ pIC50 9.0 (IC50 1x10-9 M) [6]
Description: in association with cyclin T1
TG02 Hs Inhibition 8.5 pIC50 10
⤷ pIC50 8.5 (IC50 3x10-9 M) [10]
dinaciclib Hs Inhibition 8.4 pIC50 17
⤷ pIC50 8.4 (IC50 4x10-9 M) [17]
THAL-SNS-032 Hs Inhibition 8.4 pIC50 20
⤷ pIC50 8.4 (IC50 4x10-9 M) [20]
Description: Biochemical inhibition of CDK9/CycT1.
AT-7519 Hs Inhibition >8.0 pIC50 24
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [24]
riviciclib Hs Inhibition 7.7 pIC50 16
⤷ pIC50 7.7 (IC50 2x10-8 M) [16]
Description: CDK9/cyclin T1 complex
AZD5438 Hs Inhibition 7.7 pIC50 5
⤷ pIC50 7.7 (IC50 2x10-8 M) [5]
Description: CDK9/cyclin T complex.
voruciclib Hs Inhibition 7.7 pIC50 21
⤷ pIC50 7.7 (IC50 2.2x10-8 M) [21]
Description: Inhibition of CDK9/cyclinT.
CDK inhibitor 4.35 Hs Inhibition 7.6 pIC50 14
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [14]
Description: Inhibition of CDK9/cyclin T1 complex.
compound 89S [PMID: 19115845] Hs Inhibition 7.6 pIC50 19
⤷ pIC50 7.6 (IC50 2.8x10-8 M) [19]
Description: CDK9/cyclin T complex
kinase inhibitor 2 [PMID: 30199702] Hs Inhibition 7.3 pIC50 7
⤷ pIC50 7.3 (IC50 4.9x10-8 M) [7]
Description: CDK9/cyclin T
trilaciclib Hs Inhibition 7.3 pIC50 4
⤷ pIC50 7.3 (IC50 5x10-8 M) [4]
Description: Inhibition of CDK9/cyclinT
BS-194 Hs Inhibition 7.1 pIC50 11
⤷ pIC50 7.1 (IC50 9x10-8 M) [11]
fadraciclib Hs Inhibition 7.0 pIC50 23
⤷ pIC50 7.0 (IC50 1x10-7 M) [23]
Description: Inhibition of CDK9/cyclin T1
compound 18 [PMID: 20873740] Hs Inhibition 6.4 pIC50 18
⤷ pIC50 6.4 (IC50 3.94x10-7 M) [18]
ICEC0942 Hs Inhibition 5.9 pIC50 22
⤷ pIC50 5.9 (IC50 1.2x10-6 M) [22]
Description: In a biochemical assay.
CGP74514A Hs Inhibition 5.8 pIC50 15
⤷ pIC50 5.8 (IC50 1.4x10-6 M) [15]
Description: In vitro inhibition of human CDK9/cyclin T.
SU9516 Hs Inhibition 5.8 pIC50 15
⤷ pIC50 5.8 (IC50 1.5x10-6 M) [15]
Description: In vitro inhibition of CDK9/cyclin T.
milciclib Hs Inhibition 5.1 pIC50 15
⤷ pIC50 5.1 (IC50 7.7x10-6 M) [15]
Description: In vitro inhibition of CDK9/cyclin T.
CDK12 inhibitor 2 Hs Inhibition 4.8 pIC50 13
⤷ pIC50 4.8 (IC50 1.6x10-5 M) [13]
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: 8,25
Key to terms and symbols Click column headers to sort
Target used in screen: CDK9
Ligand Sp. Type Action Value Parameter
AT-7519 Hs Inhibitor Inhibition 8.2 pKd
alvocidib Hs Inhibitor Inhibition 8.2 pKd
R547 Hs Inhibitor Inhibition 7.8 pKd
BMS-387032 Hs Inhibitor Inhibition 7.1 pKd
staurosporine Hs Inhibitor Inhibition 7.0 pKd
A-674563 Hs Inhibitor Inhibition 6.7 pKd
AST-487 Hs Inhibitor Inhibition 6.7 pKd
lestaurtinib Hs Inhibitor Inhibition 6.3 pKd
enzastaurin Hs Inhibitor Inhibition 5.9 pKd
foretinib Hs Inhibitor Inhibition 5.8 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,9
Key to terms and symbols Click column headers to sort
Target used in screen: CDK9-cyclin T1/CDK9-cyclin T1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 1.4 1.0 1.0
SB 218078 Hs Inhibitor Inhibition 8.5 71.0 66.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 15.6 0.0 -1.0
PKR inhibitor Hs Inhibitor Inhibition 16.0 5.0 3.0
alsterpaullone Hs Inhibitor Inhibition 22.6 1.0 2.0
Cdk/Crk inhibitor Hs Inhibitor Inhibition 22.7 2.0 0.0
JNK inhibitor V Hs Inhibitor Inhibition 23.3 8.0 3.0
K-252a Hs Inhibitor Inhibition 26.4 10.0 2.0
JNJ-7706621 Hs Inhibitor Inhibition 27.6 0.0 0.0
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 28.6 1.0 0.0
Target used in screen: nd/CDK9 cyclin K
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 7.5
staurosporine Hs Inhibitor Inhibition 9.2
SB 218078 Hs Inhibitor Inhibition 15.8
Cdk/Crk inhibitor Hs Inhibitor Inhibition 21.6
alsterpaullone 2-cyanoethyl Hs Inhibitor Inhibition 23.7
PKR inhibitor Hs Inhibitor Inhibition 23.8
alsterpaullone Hs Inhibitor Inhibition 24.2
K-252a Hs Inhibitor Inhibition 25.4
JNK inhibitor V Hs Inhibitor Inhibition 26.6
JNJ-7706621 Hs Inhibitor Inhibition 27.4
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0071345 cellular response to cytokine stimulus IDA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:2001168 positive regulation of histone H2B ubiquitination IMP

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Barsanti PA et al.. (2011) Pyridine and pyrazine derivatives as protein kinase modulators. Patent number: WO2011012661. Assignee: Novartis Ag. Priority date: 30/07/2009. Publication date: 03/02/2011.

3. Baumli S, Lolli G, Lowe ED, Troiani S, Rusconi L, Bullock AN, Debreczeni JE, Knapp S, Johnson LN. (2008) The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J., 27 (13): 1907-18. [PMID:18566585]

4. Bisi JE, Sorrentino JA, Roberts PJ, Tavares FX, Strum JC. (2016) Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression. Mol. Cancer Ther., 15 (5): 783-93. [PMID:26826116]

5. Byth KF, Thomas A, Hughes G, Forder C, McGregor A, Geh C, Oakes S, Green C, Walker M, Newcombe N et al.. (2009) AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol. Cancer Ther., 8 (7): 1856-66. [PMID:19509270]

6. Cirstea D, Hideshima T, Santo L, Eda H, Mishima Y, Nemani N, Hu Y, Mimura N, Cottini F, Gorgun G et al.. (2013) Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia, 27 (12): 2366-75. [PMID:23807770]

7. Compain G, Oumata N, Clarhaut J, Péraudeau E, Renoux B, Galons H, Papot S. (2018) A β-glucuronidase-responsive albumin-binding prodrug for potential selective kinase inhibitor-based cancer chemotherapy. Eur J Med Chem, 158: 1-6. [PMID:30199702]

8. 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]

9. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

10. Goh KC, Novotny-Diermayr V, Hart S, Ong LC, Loh YK, Cheong A, Tan YC, Hu C, Jayaraman R, William AD et al.. (2012) TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia, 26 (2): 236-43. [PMID:21860433]

11. Heathcote DA, Patel H, Kroll SH, Hazel P, Periyasamy M, Alikian M, Kanneganti SK, Jogalekar AS, Scheiper B, Barbazanges M et al.. (2010) A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration. J. Med. Chem., 53 (24): 8508-22. [PMID:21080703]

12. Hole AJ, Baumli S, Shao H, Shi S, Huang S, Pepper C, Fischer PM, Wang S, Endicott JA, Noble ME. (2013) Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. J. Med. Chem., 56 (3): 660-70. [PMID:23252711]

13. 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]

14. Jorda R, Havlíček L, Šturc A, Tušková D, Daumová L, Alam M, Škerlová J, Nekardová M, Peřina M, Pospíšil T et al.. (2019) 3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models. J. Med. Chem., 62 (9): 4606-4623. DOI: 10.1021/acs.jmedchem.9b00189 [PMID:30943029]

15. Jorda R, Hendrychová D, Voller J, Řezníčková E, Gucký T, Kryštof V. (2018) How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?. J. Med. Chem., 61 (20): 9105-9120. [PMID:30234987]

16. Joshi KS, Rathos MJ, Joshi RD, Sivakumar M, Mascarenhas M, Kamble S, Lal B, Sharma S. (2007) In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol. Cancer Ther., 6 (3): 918-25. [PMID:17363486]

17. Martin MP, Olesen SH, Georg GI, Schönbrunn E. (2013) Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. ACS Chem. Biol., 8 (11): 2360-5. [PMID:24007471]

18. Menichincheri M, Albanese C, Alli C, Ballinari D, Bargiotti A, Caldarelli M, Ciavolella A, Cirla A, Colombo M, Colotta F et al.. (2010) Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding. J. Med. Chem., 53 (20): 7296-315. [PMID:20873740]

19. Menichincheri M, Bargiotti A, Berthelsen J, Bertrand JA, Bossi R, Ciavolella A, Cirla A, Cristiani C, Croci V, D'Alessio R et al.. (2009) First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J. Med. Chem., 52 (2): 293-307. [PMID:19115845]

20. Olson CM, Jiang B, Erb MA, Liang Y, Doctor ZM, Zhang Z, Zhang T, Kwiatkowski N, Boukhali M, Green JL et al.. (2018) Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat. Chem. Biol., 14 (2): 163-170. [PMID:29251720]

21. 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]

22. Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A et al.. (2018) ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment. Mol. Cancer Ther., 17 (6): 1156-1166. [PMID:29545334]

23. Sheldrake PW, Atrash B, Green S, Mcdonald E, Frame S. (2008) 2, 6, 9-substituted purine derivatives having anti proliferative properties. Patent number: WO2008122767A2. Assignee: Cyclacel Limited, Cancer Research Technology Limited. Priority date: 04/04/2007. Publication date: 16/10/2008.

24. Squires MS, Feltell RE, Wallis NG, Lewis EJ, Smith DM, Cross DM, Lyons JF, Thompson NT. (2009) Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol. Cancer Ther., 8 (2): 324-32. [PMID:19174555]

25. 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

CDK9 subfamily: cyclin dependent kinase 9. Last modified on 12/11/2019. Accessed on 29/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1981.