Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQYF7G)

• DTT 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
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Lung cancer [ICD-11: 2C25]
  Malignant haematopoietic neoplasm [ICD-11: 2B33]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• BioChemical Class: Kinase
• UniProt ID: CDK7_HUMAN
• TTD ID: T58449
• EC Number: EC 2.7.11.22
• Sequence:
  MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSEAKDGINRTAL
  REIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEVIIKDNSLVLTPSHIKAYMLM
  TLQGLEYLHQHWILHRDLKPNNLLLDENGVLKLADFGLAKSFGSPNRAYTHQVVTRWYRA
  PELLFGARMYGVGVDMWAVGCILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDM
  CSLPDYVTFKSFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPG
  PTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF
• 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.
• KEGG Pathway:
  Basal transcription factors (hsa03022)
  Nucleotide excision repair (hsa03420)
  Cell cycle (hsa04110)
• Reactome Pathway:
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Cyclin E associated events during G1/S transition (R-HSA-69202)
  Cyclin D associated events in G1 (R-HSA-69231)
  Cyclin A/B1 associated events during G2/M transition (R-HSA-69273)
  Cyclin A (R-HSA-69656)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  NoRC negatively regulates rRNA expression (R-HSA-427413)

Molecular Interaction Atlas (MIA) of This DTT

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
R-roscovitine	DMSH108	Non-small-cell lung cancer	2C25.Y	Phase 2	[1]
BTX-A51	DMC8XHQ	Advanced solid tumour	2A00-2F9Z	Phase 1	[2]
LY3405105	DMB51K2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]
SNS-032	DMEITAS	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4], [5]
SY-1365	DMK48PM	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
SY-5609	DMNW3LH	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]

6 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Oxazolyl methylthiothiazole derivative 1	DMZM6FW	N. A.	N. A.	Patented	[8]
PMID26161698-Compound-34	DMTIM1E	N. A.	N. A.	Patented	[8]
Pyrazolo-triazine derivative 1	DMTD3C1	N. A.	N. A.	Patented	[8]
Pyrazolo-triazine derivative 2	DML6V78	N. A.	N. A.	Patented	[8]
Roscovitine derivative 1	DMD1G3Z	N. A.	N. A.	Patented	[8]
Tricyclic benzimidazole derivative 1	DM5SD9E	N. A.	N. A.	Patented	[8]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
R547	DMK25FU	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[1]
ZK 304709	DMJ9R4A	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[1]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2,5-dichloro-N-p-tolylthiophene-3-sulfonamide	DMU5J8Y	Discovery agent	N.A.	Investigative	[9]
NU6140	DMCUSG3	Discovery agent	N.A.	Investigative	[10]
PF-228	DM32FKD	Discovery agent	N.A.	Investigative	[11]
Phosphonothreonine	DMTFHPI	Discovery agent	N.A.	Investigative	[12]
RGB-286147	DMP08BY	Discovery agent	N.A.	Investigative	[13]
THZ1	DMU10FE	Nasopharyngeal carcinoma	2B6B	Investigative	[14]

References

• [1] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [2] Clinical pipeline report, company report or official report of BioTheryX.
• [3] CDK7 inhibitors as anticancer drugs. Cancer Metastasis Rev. 2020 Sep;39(3):805-823.
• [4] Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45.
• [5] Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 2009 Mar;16(2):36-43.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Clinical pipeline report, company report or official report of Syros Pharmaceuticals.
• [8] Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.
• [9] Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases, Bioorg. Med. Chem. Lett. 20(13):3863-3867 (2010).
• [10] 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.
• [11] Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52.
• [12] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [13] 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.
• [14] Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014 Jul 31;511(7511):616-20.