Target Information
Target General Information | Top | |||||
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Target ID |
T58449
(Former ID: TTDC00094)
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Target Name |
Cyclin-dependent kinase 7 (CDK7)
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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
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Gene Name |
CDK7
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Lung cancer [ICD-11: 2C25] | |||||
2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
3 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
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.
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BioChemical Class |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.11.22
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Sequence |
MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSEAKDGINRTAL
REIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEVIIKDNSLVLTPSHIKAYMLM TLQGLEYLHQHWILHRDLKPNNLLLDENGVLKLADFGLAKSFGSPNRAYTHQVVTRWYRA PELLFGARMYGVGVDMWAVGCILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDM CSLPDYVTFKSFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPG PTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T46NT6 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
1 | R-roscovitine | Drug Info | Phase 2 | Non-small-cell lung cancer | [2], [3] | |
2 | BTX-A51 | Drug Info | Phase 1 | Non-hodgkin lymphoma | [4] | |
3 | LY3405105 | Drug Info | Phase 1 | Solid tumour/cancer | [5] | |
4 | SNS-032 | Drug Info | Phase 1 | Solid tumour/cancer | [6], [7] | |
5 | SY-1365 | Drug Info | Phase 1 | Solid tumour/cancer | [8] | |
6 | SY-5609 | Drug Info | Phase 1 | Solid tumour/cancer | [9] | |
Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
1 | R547 | Drug Info | Discontinued in Phase 1 | Advanced solid tumour | [10], [11] | |
2 | ZK 304709 | Drug Info | Discontinued in Phase 1 | Advanced solid tumour | [12] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 20 Inhibitor drugs | + | ||||
1 | R-roscovitine | Drug Info | [1] | |||
2 | BTX-A51 | Drug Info | [13] | |||
3 | LY3405105 | Drug Info | [14] | |||
4 | SNS-032 | Drug Info | [7], [15] | |||
5 | SY-1365 | Drug Info | [8] | |||
6 | SY-5609 | Drug Info | [16] | |||
7 | Oxazolyl methylthiothiazole derivative 1 | Drug Info | [17] | |||
8 | PMID26161698-Compound-34 | Drug Info | [17] | |||
9 | Pyrazolo-triazine derivative 1 | Drug Info | [17] | |||
10 | Pyrazolo-triazine derivative 2 | Drug Info | [17] | |||
11 | Roscovitine derivative 1 | Drug Info | [17] | |||
12 | Tricyclic benzimidazole derivative 1 | Drug Info | [17] | |||
13 | R547 | Drug Info | [1] | |||
14 | ZK 304709 | Drug Info | [1] | |||
15 | 2,5-dichloro-N-p-tolylthiophene-3-sulfonamide | Drug Info | [18] | |||
16 | NU6140 | Drug Info | [19] | |||
17 | PF-228 | Drug Info | [20] | |||
18 | Phosphonothreonine | Drug Info | [21] | |||
19 | RGB-286147 | Drug Info | [22] | |||
20 | THZ1 | Drug Info | [23] |
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-interacting Proteins |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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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 | ClinicalTrials.gov (NCT04872166) A Study of BTX-A51 in People With Advanced Solid Tumor or Non-Hodgkin Lymphoma. U.S. National Institutes of Health. | |||||
REF 5 | ClinicalTrials.gov (NCT03770494) A Study of LY3405105 in Participants With Advanced Cancer. U.S. National Institutes of Health. | |||||
REF 6 | 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 7 | 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 8 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 9 | ClinicalTrials.gov (NCT04247126) A Study of SY 5609, a Selective CDK7 Inhibitor, in Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
REF 10 | 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 11 | 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 12 | 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 13 | Clinical pipeline report, company report or official report of BioTheryX. | |||||
REF 14 | CDK7 inhibitors as anticancer drugs. Cancer Metastasis Rev. 2020 Sep;39(3):805-823. | |||||
REF 15 | Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 2009 Mar;16(2):36-43. | |||||
REF 16 | Clinical pipeline report, company report or official report of Syros Pharmaceuticals. | |||||
REF 17 | Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70. | |||||
REF 18 | Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases, Bioorg. Med. Chem. Lett. 20(13):3863-3867 (2010). | |||||
REF 19 | 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 20 | Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52. | |||||
REF 21 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
REF 22 | 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 23 | Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014 Jul 31;511(7511):616-20. |
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