Target General Infomation
Target ID
T58449 (Former ID: TTDC00094)
Target Name
Cyclin-dependent kinase 7 (CDK7)
Synonyms
TFIIH basal transcription factor complex kinase subunit; Serine/threonine-protein kinase 1; P39 Mo15; MO15; Cell division protein kinase 7; CDKN7; CDK-activating kinase 1; CDK-activating kinase; CAK1; CAK; 39 kDa protein kinase
Gene Name
CDK7
Target Type
Clinical trial target
[1]
Disease [+] 2 Target-related Diseases +
1 Lung cancer [ICD-11: 2C25]
2 Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Function
Cyclin-dependent kinases (CDKs) are activated by the binding to a cyclin and mediate the progression through the cell cycle. Each different complex controls a specific transition between 2 subsequent phases in the cell cycle. Required for both activation and complex formation of CDK1/cyclin-B during G2-M transition, and for activation of CDK2/cyclins during G1-S transition (but not complex formation). CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Phosphorylates SPT5/SUPT5H, SF1/NR5A1, POLR2A, p53/TP53, CDK1, CDK2, CDK4, CDK6 and CDK11B/CDK11. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation, thus regulating cell cycle progression. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Phosphorylation of POLR2A in complex with DNA promotes transcription initiation by triggering dissociation from DNA. Its expression and activity are constant throughout the cell cycle. Upon DNA damage, triggers p53/TP53 activation by phosphorylation, but is inactivated in turn by p53/TP53; this feedback loop may lead to an arrest of the cell cycle and of the transcription, helping in cell recovery, or to apoptosis. Required for DNA-bound peptides-mediated transcription and cellular growth inhibition. Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription.
BioChemical Class
Kinase
UniProt ID
CDK7_HUMAN
EC Number
EC 2.7.11.22
Sequence
MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSEAKDGINRTAL
REIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEVIIKDNSLVLTPSHIKAYMLM
TLQGLEYLHQHWILHRDLKPNNLLLDENGVLKLADFGLAKSFGSPNRAYTHQVVTRWYRA
PELLFGARMYGVGVDMWAVGCILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDM
CSLPDYVTFKSFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPG
PTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF
Drugs and Modes of Action
Clinical Trial Drug(s) [+] 3 Clinical Trial Drugs +
1 R-roscovitine Drug Info Phase 2 Non-small-cell lung cancer [2], [3]
2 SNS-032 Drug Info Phase 1 Solid tumour/cancer [4], [5]
3 SY-1365 Drug Info Phase 1 Solid tumour/cancer [6]
Discontinued Drug(s) [+] 2 Discontinued Drugs +
1 R547 Drug Info Discontinued in Phase 1 Advanced solid tumour [7], [8]
2 ZK 304709 Drug Info Discontinued in Phase 1 Advanced solid tumour [9]
Mode of Action [+] 1 Modes of Action +
Inhibitor [+] 17 Inhibitor drugs +
1 R-roscovitine Drug Info [1]
2 SNS-032 Drug Info [5], [10]
3 SY-1365 Drug Info [6]
4 Oxazolyl methylthiothiazole derivative 1 Drug Info [11]
5 PMID26161698-Compound-34 Drug Info [11]
6 Pyrazolo-triazine derivative 1 Drug Info [11]
7 Pyrazolo-triazine derivative 2 Drug Info [11]
8 Roscovitine derivative 1 Drug Info [11]
9 Tricyclic benzimidazole derivative 1 Drug Info [11]
10 R547 Drug Info [1]
11 ZK 304709 Drug Info [1]
12 2,5-dichloro-N-p-tolylthiophene-3-sulfonamide Drug Info [12]
13 NU6140 Drug Info [13]
14 PF-228 Drug Info [14]
15 Phosphonothreonine Drug Info [15]
16 RGB-286147 Drug Info [16]
17 THZ1 Drug Info [17]
Target Regulators
Target-interacting Proteins
Target Affiliated Biological Pathways
KEGG Pathway [+] 3 KEGG Pathways +
1 Basal transcription factors
2 Nucleotide excision repair
3 Cell cycle
NetPath Pathway [+] 2 NetPath Pathways +
1 TCR Signaling Pathway
2 RANKL Signaling Pathway
PID Pathway [+] 1 PID Pathways +
1 Retinoic acid receptors-mediated signaling
Reactome [+] 9 Reactome Pathways +
1 NoRC negatively regulates rRNA expression
2 Formation of TC-NER Pre-Incision Complex
3 Dual incision in TC-NER
4 Gap-filling DNA repair synthesis and ligation in TC-NER
5 Cyclin E associated events during G1/S transition
6 Cyclin D associated events in G1
7 Cyclin A/B1 associated events during G2/M transition
8 Cyclin A:Cdk2-associated events at S phase entry
9 RNA Polymerase I Transcription Initiation
WikiPathways [+] 13 WikiPathways +
1 G1 to S cell cycle control
2 Eukaryotic Transcription Initiation
3 Cardiac Hypertrophic Response
4 S Phase
5 HIV Life Cycle
6 Integrated Breast Cancer Pathway
7 Nucleotide Excision Repair
8 RNA Polymerase II Transcription
9 RNA Polymerase I, RNA Polymerase III, and Mitochondrial Transcription
10 mRNA Capping
11 Mitotic G2-G2/M phases
12 Mitotic G1-G1/S phases
13 MicroRNAs in cardiomyocyte hypertrophy
Target-Related Models and Studies
Target Validation
References
REF 1 Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
REF 2 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6035).
REF 3 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010117)
REF 4 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5670).
REF 5 Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45.
REF 6 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 7 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5707).
REF 8 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018924)
REF 9 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022386)
REF 10 Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 2009 Mar;16(2):36-43.
REF 11 Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
REF 12 Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases, Bioorg. Med. Chem. Lett. 20(13):3863-3867 (2010).
REF 13 Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. Mol Cancer Ther. 2005 Sep;4(9):1328-37.
REF 14 Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52.
REF 15 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 16 A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8.
REF 17 Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014 Jul 31;511(7511):616-20.

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