Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAO19PQ)

DOT Name	Cyclin-dependent kinase 7 (CDK7)
Synonyms	EC 2.7.11.22; EC 2.7.11.23; 39 kDa protein kinase; p39 Mo15; CDK-activating kinase 1; Cell division protein kinase 7; Serine/threonine-protein kinase 1; TFIIH basal transcription factor complex kinase subunit
Gene Name	CDK7
UniProt ID	CDK7_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1UA2; 6O9L; 6XBZ; 6XD3; 7B5O; 7B5Q; 7EGB; 7EGC; 7ENA; 7ENC; 7LBM; 7NVR; 8BVW; 8BYQ; 8GXQ; 8GXS; 8ORM; 8P4Z; 8P6V; 8P6Y
EC Number	2.7.11.22; 2.7.11.23
Pfam ID	PF00069
Sequence	MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSEAKDGINRTAL REIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEVIIKDNSLVLTPSHIKAYMLM TLQGLEYLHQHWILHRDLKPNNLLLDENGVLKLADFGLAKSFGSPNRAYTHQVVTRWYRA PELLFGARMYGVGVDMWAVGCILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDM CSLPDYVTFKSFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPG PTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF
Function	Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. 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.
Tissue Specificity	Ubiquitous.
KEGG Pathway	Basal transcription factors (hsa03022 ) Nucleotide excision repair (hsa03420 ) Cell cycle (hsa04110 )
Reactome Pathway	Formation of the Early Elongation Complex (R-HSA-113418 ) Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152 ) Formation of the HIV-1 Early Elongation Complex (R-HSA-167158 ) RNA Pol II CTD phosphorylation and interaction with CE during HIV infection (R-HSA-167160 ) HIV Transcription Initiation (R-HSA-167161 ) RNA Polymerase II HIV Promoter Escape (R-HSA-167162 ) Transcription of the HIV genome (R-HSA-167172 ) Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200 ) Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246 ) NoRC negatively regulates rRNA expression (R-HSA-427413 ) Formation of Incision Complex in GG-NER (R-HSA-5696395 ) RNA Polymerase II Pre-transcription Events (R-HSA-674695 ) Formation of TC-NER Pre-Incision Complex (R-HSA-6781823 ) Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827 ) Dual incision in TC-NER (R-HSA-6782135 ) Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210 ) TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648 ) RNA polymerase II transcribes snRNA genes (R-HSA-6807505 ) Cyclin E associated events during G1/S transition (R-HSA-69202 ) Cyclin D associated events in G1 (R-HSA-69231 ) Cyclin A/B1/B2 associated events during G2/M transition (R-HSA-69273 ) Cyclin A (R-HSA-69656 ) mRNA Capping (R-HSA-72086 ) RNA Polymerase I Transcription Initiation (R-HSA-73762 ) RNA Polymerase I Promoter Escape (R-HSA-73772 ) RNA Polymerase II Promoter Escape (R-HSA-73776 ) RNA Polymerase II Transcription Pre-Initiation And Promoter Opening (R-HSA-73779 ) RNA Polymerase I Transcription Termination (R-HSA-73863 ) RNA Polymerase II Transcription Initiation (R-HSA-75953 ) RNA Polymerase II Transcription Elongation (R-HSA-75955 ) RNA Polymerase II Transcription Initiation And Promoter Clearance (R-HSA-76042 ) RNA Pol II CTD phosphorylation and interaction with CE (R-HSA-77075 ) RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236 ) Formation of RNA Pol II elongation complex (R-HSA-112382 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

23 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cyclin-dependent kinase 7 (CDK7).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-dependent kinase 7 (CDK7).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cyclin-dependent kinase 7 (CDK7).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cyclin-dependent kinase 7 (CDK7).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cyclin-dependent kinase 7 (CDK7).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cyclin-dependent kinase 7 (CDK7).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cyclin-dependent kinase 7 (CDK7).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cyclin-dependent kinase 7 (CDK7).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Cyclin-dependent kinase 7 (CDK7).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cyclin-dependent kinase 7 (CDK7).	[10]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the activity of Cyclin-dependent kinase 7 (CDK7).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Cyclin-dependent kinase 7 (CDK7).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cyclin-dependent kinase 7 (CDK7).	[12]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Cyclin-dependent kinase 7 (CDK7).	[13]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Cyclin-dependent kinase 7 (CDK7).	[14]
BMS-3870032	DMCWIBU	Preclinical	BMS-3870032 decreases the activity of Cyclin-dependent kinase 7 (CDK7).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cyclin-dependent kinase 7 (CDK7).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cyclin-dependent kinase 7 (CDK7).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cyclin-dependent kinase 7 (CDK7).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Cyclin-dependent kinase 7 (CDK7).	[20]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Cyclin-dependent kinase 7 (CDK7).	[21]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Cyclin-dependent kinase 7 (CDK7).	[22]
Wogonin	DMGCF51	Investigative	Wogonin decreases the activity of Cyclin-dependent kinase 7 (CDK7).	[23]
------------------------------------------------------------------------------------


⏷ Show the Full List of 23 Drug(s)

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cyclin-dependent kinase 7 (CDK7).	[15]
------------------------------------------------------------------------------------

References

1	Effects of valproic acid and levetiracetam on viability and cell cycle regulatory genes expression in the OVCAR-3 cell line. Pharmacol Rep. 2012;64(1):157-65. doi: 10.1016/s1734-1140(12)70742-9.
2	Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
3	Caffeine disrupts ataxia telangiectasia mutated gene-related pathways and exacerbates acetaminophen toxicity in human fetal immortalized hepatocytes. Toxicology. 2021 Jun 15;457:152811. doi: 10.1016/j.tox.2021.152811. Epub 2021 May 7.
4	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
5	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
6	Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
7	Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
8	Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
9	Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
10	Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-alpha, CH11 and CYC202. Endocr Relat Cancer. 2007 Jun;14(2):305-15. doi: 10.1677/ERC-06-0003.
11	Cell cycle G2/M arrest and activation of cyclin-dependent kinases associated with low-dose paclitaxel-induced sub-G1 apoptosis. Apoptosis. 1997;2(5):463-70. doi: 10.1023/a:1026422111457.
12	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
13	Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
14	Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells. Mutat Res. 2005 Aug 4;575(1-2):47-60. doi: 10.1016/j.mrfmmm.2005.03.002. Epub 2005 Apr 26.
15	Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
16	Characterization of molecular and cellular functions of the cyclin-dependent kinase CDK9 using a novel specific inhibitor. Br J Pharmacol. 2014 Jan;171(1):55-68. doi: 10.1111/bph.12408.
17	Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
18	A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
19	Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
20	Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
21	Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
22	Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
23	Wogonin alleviates BaP-induced DNA damage and oxidative stress in human airway epithelial cells by dual inhibiting CYP1A1 activity and expression. Environ Toxicol. 2023 Nov;38(11):2717-2729. doi: 10.1002/tox.23907. Epub 2023 Jul 29.