cyclin dependent kinase 7 | CDK7 subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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cyclin dependent kinase 7

target has curated data in GtoImmuPdb

Target id: 1979

Nomenclature: cyclin dependent kinase 7

Abbreviated Name: CDK7

Family: CDK7 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 - 346 5q12.1 CDK7 cyclin dependent kinase 7
Mouse - 346 13 D1 Cdk7 cyclin-dependent kinase 7
Rat - - 2 q12 Cdk7 cyclin-dependent kinase 7
Previous and Unofficial Names
CAK1 | CDKN7 | STK1 | 39 kDa protein kinase | CDK-activating kinase 1 | cell division protein kinase 7 | CRK4 | protein-tyrosine kinase MPK-7 | TFIIH basal transcription factor complex kinase subunit
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 CDK7
PDB Id:  1UA2
Resolution:  3.02Å
Species:  Human
References:  17
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
SY-1365 Hs Inhibition >7.8 pKi 12
pKi >7.8 (Ki <1.74x10-8 M) [12]
THZ1 Hs Inhibition 8.5 pIC50 15
pIC50 8.5 (IC50 3.2x10-9 M) [15]
BS-181 Hs Inhibition 7.7 pIC50 1
pIC50 7.7 (IC50 2.1x10-8 M) [1]
Description: Evaluated using purified recombinant CDK7/CycH/MAT1 complex and measuring free ATP remaining in the reaction using a luciferase assay.
ICEC0942 Hs Inhibition 7.4 pIC50 19
pIC50 7.4 (IC50 4x10-8 M) [19]
Description: In a biochemical assay.
RGB-286638 Hs Inhibition 7.4 pIC50 6
pIC50 7.4 (IC50 4.4x10-8 M) [6]
Description: in association with cyclin H
Cdk/Crk inhibitor Hs Inhibition 7.2 pIC50 8
pIC50 7.2 (IC50 7.1x10-8 M) [8]
Description: CDK7/cyclin H
milciclib Hs Inhibition 6.6 – 6.8 pIC50 4,14
pIC50 6.8 (IC50 1.5x10-7 M) [4]
Description: CDK7/cyclin H complex
pIC50 6.6 (IC50 2.7x10-7 M) [14]
Description: In vitro inhibition of CDK7/cyclin H.
BS-194 Hs Inhibition 6.6 pIC50 10
pIC50 6.6 (IC50 2.5x10-7 M) [10]
CGP74514A Hs Inhibition 6.6 pIC50 14
pIC50 6.6 (IC50 2.79x10-7 M) [14]
Description: In vitro inhibition of human CDK7/cyclin H.
THAL-SNS-032 Hs Inhibition 6.4 pIC50 18
pIC50 6.4 (IC50 3.98x10-7 M) [18]
Description: Inhibition of CDK7/CycH/MNAT1.
SU9516 Hs Inhibition 6.0 pIC50 14
pIC50 6.0 (IC50 9.05x10-7 M) [14]
Description: In vitro inhibition of CDK7/cyclin H.
Cdk2 inhibitor IV Hs Inhibition 5.4 pIC50 20
pIC50 5.4 (IC50 3.9x10-6 M) [20]
Description: CDK7/cyclin H complex used in assay
trilaciclib Hs Inhibition 5.3 pIC50 3
pIC50 5.3 (IC50 4.64x10-6 M) [3]
Description: Inhibition of CDK7/cyclinM/Mat1
CDK12 inhibitor 2 Hs Inhibition <5.0 pIC50 13
pIC50 <5.0 (IC50 >1x10-5 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: 7,23

Key to terms and symbols Click column headers to sort
Target used in screen: CDK7
Ligand Sp. Type Action Value Parameter
R547 Hs Inhibitor Inhibition 9.2 pKd
AT-7519 Hs Inhibitor Inhibition 8.6 pKd
foretinib Hs Inhibitor Inhibition 8.4 pKd
AST-487 Hs Inhibitor Inhibition 8.3 pKd
alvocidib Hs Inhibitor Inhibition 7.6 pKd
BMS-387032 Hs Inhibitor Inhibition 7.5 pKd
staurosporine Hs Inhibitor Inhibition 7.3 pKd
A-674563 Hs Inhibitor Inhibition 7.2 pKd
lestaurtinib Hs Inhibitor Inhibition 7.1 pKd
fedratinib Hs Inhibitor Inhibition 6.9 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: 2,9

Key to terms and symbols Click column headers to sort
Target used in screen: CDK7-cyclin H-MAT1/CDK7-cyclin H
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 43.6 2.0 -2.0
staurosporine Hs Inhibitor Inhibition 43.8 4.0 0.5
aminopurvalanol A Hs Inhibitor Inhibition 54.7 43.0 6.0
CGP74514A Hs Inhibitor Inhibition 58.4 5.0 -1.0
purvalanol A Hs Inhibitor Inhibition 59.5 17.0 1.0
SU11274 Hs Inhibitor Inhibition 59.7 4.0 2.0
PKR inhibitor Hs Inhibitor Inhibition 60.3 15.0 3.0
Cdk/Crk inhibitor Hs Inhibitor Inhibition 60.3 15.0 1.0
SU11652 Hs Inhibitor Inhibition 72.8 15.0 2.0
GSK-3 inhibitor XIII Hs Inhibitor Inhibition 73.3 19.0 1.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Studies completed by Hong et al. (2018) indicate a role for CDK7 in rheumatoid arthritis inflammation, and experimental results show that selective inhibition of CDK7 (pharmacological or gene knock-down) suppresses the production of IL-1β and IL-6 via a NF-κB mechanism [11,24].
General Comments
CDK7 is required for transcription. It phosphorylates the C-terminal domain of RNA polymerase II which enables transcription initiation. CDK7 has emerged as an attractive oncology target since its inhibition decreases the transcript levels of oncogenic transcription factors, especially those driven by super-enhancers, and to which some cancers become addicted [5,16,21-22,25].

References

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1. Ali S, Heathcote DA, Kroll SH, Jogalekar AS, Scheiper B, Patel H, Brackow J, Siwicka A, Fuchter MJ, Periyasamy M et al.. (2009) The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity. Cancer Res., 69 (15): 6208-15. [PMID:19638587]

2. 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]

3. 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]

4. Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M, Colotta F, Croci V, D'Alessio R et al.. (2009) Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J. Med. Chem., 52 (16): 5152-63. [PMID:19603809]

5. Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, Abraham BJ, Sharma B, Yeung C, Altabef A et al.. (2014) CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell, 159 (5): 1126-1139. [PMID:25416950]

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. 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]

8. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl. Acad. Sci. U.S.A., 104 (51): 20523-8. [PMID:18077363]

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. 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]

11. Hong H, Zeng Y, Jian W, Li L, Lin L, Mo Y, Liu M, Fang S, Xia Y. (2018) CDK7 inhibition suppresses rheumatoid arthritis inflammation via blockage of NF-κB activation and IL-1β/IL-6 secretion. J. Cell. Mol. Med., 22 (2): 1292-1301. [PMID:29083085]

12. Hu S, Marineau JJ, Rajagopal N, Hamman KB, Choi YJ, Schmidt DR, Ke N, Johannessen L, Bradley MJ, Orlando DA et al.. (2019) Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7. Cancer Res., 79 (13): 3479-3491. [PMID:31064851]

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, 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]

15. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A, Ramaswamy S, Tesar B et al.. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature, 511 (7511): 616-20. [PMID:25043025]

16. Li B, Ni Chonghaile T, Fan Y, Madden SF, Klinger R, O'Connor AE, Walsh L, O'Hurley G, Mallya Udupi G, Joseph J et al.. (2017) Therapeutic Rationale to Target Highly Expressed CDK7 Conferring Poor Outcomes in Triple-Negative Breast Cancer. Cancer Res., 77 (14): 3834-3845. [PMID:28455421]

17. Lolli G, Lowe ED, Brown NR, Johnson LN. (2004) The crystal structure of human CDK7 and its protein recognition properties. Structure, 12 (11): 2067-79. [PMID:15530371]

18. 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]

19. 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]

20. Pennati M, Campbell AJ, Curto M, Binda M, Cheng Y, Wang LZ, Curtin N, Golding BT, Griffin RJ, Hardcastle IR et al.. (2005) Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. Mol. Cancer Ther., 4 (9): 1328-37. [PMID:16170024]

21. Wang C, Jin H, Gao D, Wang L, Evers B, Xue Z, Jin G, Lieftink C, Beijersbergen RL, Qin W et al.. (2018) A CRISPR screen identifies CDK7 as a therapeutic target in hepatocellular carcinoma. Cell Res., 28 (6): 690-692. [PMID:29507396]

22. Wang Y, Zhang T, Kwiatkowski N, Abraham BJ, Lee TI, Xie S, Yuzugullu H, Von T, Li H, Lin Z et al.. (2015) CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell, 163 (1): 174-86. [PMID:26406377]

23. 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]

24. Xia Y, Lin LY, Liu ML, Wang Z, Hong HH, Guo XG, Gao GQ. (2015) Selective inhibition of CDK7 ameliorates experimental arthritis in mice. Clin. Exp. Med., 15 (3): 269-75. [PMID:25149277]

25. Zhang Z, Peng H, Wang X, Yin X, Ma P, Jing Y, Cai MC, Liu J, Zhang M, Zhang S et al.. (2017) Preclinical Efficacy and Molecular Mechanism of Targeting CDK7-Dependent Transcriptional Addiction in Ovarian Cancer. Mol. Cancer Ther., 16 (9): 1739-1750. [PMID:28572168]

How to cite this page

CDK7 subfamily: cyclin dependent kinase 7. Last modified on 12/11/2019. Accessed on 08/12/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1979.