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cyclin dependent kinase 7

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1979

Nomenclature: cyclin dependent kinase 7

Abbreviated Name: CDK7

Family: CDK7 subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 346 5q13.2 CDK7 cyclin dependent kinase 7
Mouse - 346 13 53.23 cM Cdk7 cyclin dependent kinase 7
Rat - 329 2q12 Cdk7 cyclin-dependent kinase 7
Previous and Unofficial Names Click here for help
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 Click here for help
Alphafold P50613 (Hs), Q03147 (Mm), P51952 (Rn)
BRENDA 2.7.11.22, 2.7.11.23
ChEMBL Target CHEMBL3055 (Hs), CHEMBL2176816 (Mm)
Ensembl Gene ENSG00000134058 (Hs), ENSMUSG00000069089 (Mm), ENSRNOG00000018510 (Rn)
Entrez Gene 1022 (Hs), 12572 (Mm), 171150 (Rn)
Human Protein Atlas ENSG00000134058 (Hs)
KEGG Enzyme 2.7.11.22, 2.7.11.23
KEGG Gene hsa:1022 (Hs), mmu:12572 (Mm), rno:171150 (Rn)
OMIM 601955 (Hs)
Pharos P50613 (Hs)
RefSeq Nucleotide NM_001799 (Hs), NM_009874 (Mm)
RefSeq Protein NP_001790 (Hs), NP_034004 (Mm)
UniProtKB P50613 (Hs), Q03147 (Mm), P51952 (Rn)
Wikipedia CDK7 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Human CDK7
PDB Id:  1UA2
Resolution:  3.02Å
Species:  Human
References:  18
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
SY-5609 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pKd 19
⤷ pKd 7.2 (Kd 7x10-8 M) [19]
mevociclib Small molecule or natural product Hs Inhibition >7.8 pKi 13
⤷ pKi >7.8 (Ki <1.74x10-8 M) [13]
asnuciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.0 pKi 23
⤷ pKi 7.0 (Ki 9.1x10-8 M) [23]
Description: Inhibuition of CDK7/CyclinH/MAT1 expressed in Sf21 insect cells
THZ1 Small molecule or natural product Primary target of this compound Hs Inhibition 8.5 pIC50 16
⤷ pIC50 8.5 (IC50 3.2x10-9 M) [16]
BS-181 Small molecule or natural product Primary target of this compound Click here for species-specific activity table 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.
samuraciclib Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pIC50 21
⤷ pIC50 7.4 (IC50 4x10-8 M) [21]
Description: In a biochemical assay.
RGB-286638 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 6
⤷ pIC50 7.4 (IC50 4.4x10-8 M) [6]
Description: in association with cyclin H
Cdk/Crk inhibitor Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.2 pIC50 9
⤷ pIC50 7.2 (IC50 7.1x10-8 M) [9]
Description: CDK7/cyclin H
LY3405105 Small molecule or natural product Hs Inhibition 7.0 pIC50 7
⤷ pIC50 7.0 (IC50 9.28x10-8 M) [7]
Description: Determined in an in vitro assay, using the purified human recombinant enzyme complex CDK7/CycH/MAT1
milciclib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.6 – 6.8 pIC50 4,15
⤷ pIC50 6.8 (IC50 1.5x10-7 M) [4]
Description: CDK7/cyclin H complex
pIC50 6.6 (IC50 2.7x10-7 M) [15]
Description: In vitro inhibition of CDK7/cyclin H.
BS-194 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.6 pIC50 11
⤷ pIC50 6.6 (IC50 2.5x10-7 M) [11]
CGP74514A Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.6 pIC50 15
⤷ pIC50 6.6 (IC50 2.79x10-7 M) [15]
Description: In vitro inhibition of human CDK7/cyclin H.
THAL-SNS-032 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.4 pIC50 20
⤷ pIC50 6.4 (IC50 3.98x10-7 M) [20]
Description: Inhibition of CDK7/CycH/MNAT1.
SU9516 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.0 pIC50 15
⤷ pIC50 6.0 (IC50 9.05x10-7 M) [15]
Description: In vitro inhibition of CDK7/cyclin H.
Cdk2 inhibitor IV Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.4 pIC50 22
⤷ pIC50 5.4 (IC50 3.9x10-6 M) [22]
Description: CDK7/cyclin H complex used in assay
trilaciclib Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.3 pIC50 3
⤷ pIC50 5.3 (IC50 4.64x10-6 M) [3]
Description: Inhibition of CDK7/cyclinM/Mat1
CDK12 inhibitor 2 Small molecule or natural product Click here for species-specific activity table Hs Inhibition <5.0 pIC50 14
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [14]
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: 8,26
Key to terms and symbols Click column headers to sort
Target used in screen: CDK7
Ligand Sp. Type Action Value Parameter
R547 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.2 pKd
AT-7519 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.6 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.4 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 8.3 pKd
alvocidib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.6 pKd
BMS-387032 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.5 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure 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 Click here for help
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: 2,10
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 43.6 2.0 -2.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 43.8 4.0 0.5
aminopurvalanol A Small molecule or natural product Hs Inhibitor Inhibition 54.7 43.0 6.0
CGP74514A Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 58.4 5.0 -1.0
purvalanol A Small molecule or natural product Hs Inhibitor Inhibition 59.5 17.0 1.0
SU11274 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 59.7 4.0 2.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 60.3 15.0 3.0
Cdk/Crk inhibitor Small molecule or natural product Hs Inhibitor Inhibition 60.3 15.0 1.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 72.8 15.0 2.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure 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 [12,27].
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 [5,17,24-25,28].

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. Coates DA, Montero C, Kumar B, Patel R, Remick DM, Yadav V. (2019) Compounds useful for inhibiting cdk7. Patent number: WO2019099298A1. Assignee: Eli Lilly And Company. Priority date: 16/11/2017. Publication date: 23/05/2019.

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. 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 USA, 104 (51): 20523-8. [PMID:18077363]

10. 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]

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. 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]

13. 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]

14. 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]

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. 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]

17. 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]

18. 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]

19. Marineau JJ, Hamman KB, Hu S, Alnemy S, Mihalich J, Kabro A, Whitmore KM, Winter DK, Roy S, Ciblat S et al.. (2022) Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7. J Med Chem, 65 (2): 1458-1480. [PMID:34726887]

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. 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]

22. 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]

23. Shao H, Shi S, Huang S, Hole AJ, Abbas AY, Baumli S, Liu X, Lam F, Foley DW, Fischer PM et al.. (2013) Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities. J Med Chem, 56 (3): 640-59. [PMID:23301767]

24. 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]

25. 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]

26. 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]

27. 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]

28. 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 29/07/2022. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1979.