Details of Drug Off-Target (DOT)

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

DOT Name Cyclin-dependent kinase 12 (CDK12)
Synonyms EC 2.7.11.22; EC 2.7.11.23; Cdc2-related kinase, arginine/serine-rich; CrkRS; Cell division cycle 2-related protein kinase 7; CDC2-related protein kinase 7; Cell division protein kinase 12; hCDK12
Gene Name CDK12
Related Disease
Tourette syndrome ( )
UniProt ID
CDK12_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
4CXA ; 4NST ; 4UN0 ; 5ACB ; 6B3E ; 6CKX ; 6TD3 ; 7NXK ; 8BU1 ; 8BU2 ; 8BU3 ; 8BU4 ; 8BU5 ; 8BU6 ; 8BU7 ; 8BU9 ; 8BUA ; 8BUB ; 8BUC ; 8BUD ; 8BUE ; 8BUF ; 8BUG ; 8BUH ; 8BUI ; 8BUJ ; 8BUK ; 8BUL ; 8BUM ; 8BUN ; 8BUO ; 8BUP ; 8BUQ ; 8BUR ; 8BUS ; 8BUT ; 8P81
EC Number
2.7.11.22; 2.7.11.23
Pfam ID
PF12330 ; PF00069
Sequence
MPNSERHGGKKDGSGGASGTLQPSSGGGSSNSRERHRLVSKHKRHKSKHSKDMGLVTPEA
ASLGTVIKPLVEYDDISSDSDTFSDDMAFKLDRRENDERRGSDRSDRLHKHRHHQHRRSR
DLLKAKQTEKEKSQEVSSKSGSMKDRISGSSKRSNEETDDYGKAQVAKSSSKESRSSKLH
KEKTRKERELKSGHKDRSKSHRKRETPKSYKTVDSPKRRSRSPHRKWSDSSKQDDSPSGA
SYGQDYDLSPSRSHTSSNYDSYKKSPGSTSRRQSVSPPYKEPSAYQSSTRSPSPYSRRQR
SVSPYSRRRSSSYERSGSYSGRSPSPYGRRRSSSPFLSKRSLSRSPLPSRKSMKSRSRSP
AYSRHSSSHSKKKRSSSRSRHSSISPVRLPLNSSLGAELSRKKKERAAAAAAAKMDGKES
KGSPVFLPRKENSSVEAKDSGLESKKLPRSVKLEKSAPDTELVNVTHLNTEVKNSSDTGK
VKLDENSEKHLVKDLKAQGTRDSKPIALKEEIVTPKETETSEKETPPPLPTIASPPPPLP
TTTPPPQTPPLPPLPPIPALPQQPPLPPSQPAFSQVPASSTSTLPPSTHSKTSAVSSQAN
SQPPVQVSVKTQVSVTAAIPHLKTSTLPPLPLPPLLPGDDDMDSPKETLPSKPVKKEKEQ
RTRHLLTDLPLPPELPGGDLSPPDSPEPKAITPPQQPYKKRPKICCPRYGERRQTESDWG
KRCVDKFDIIGIIGEGTYGQVYKAKDKDTGELVALKKVRLDNEKEGFPITAIREIKILRQ
LIHRSVVNMKEIVTDKQDALDFKKDKGAFYLVFEYMDHDLMGLLESGLVHFSEDHIKSFM
KQLMEGLEYCHKKNFLHRDIKCSNILLNNSGQIKLADFGLARLYNSEESRPYTNKVITLW
YRPPELLLGEERYTPAIDVWSCGCILGELFTKKPIFQANLELAQLELISRLCGSPCPAVW
PDVIKLPYFNTMKPKKQYRRRLREEFSFIPSAALDLLDHMLTLDPSKRCTAEQTLQSDFL
KDVELSKMAPPDLPHWQDCHELWSKKRRRQRQSGVVVEEPPPSKTSRKETTSGTSTEPVK
NSSPAPPQPAPGKVESGAGDAIGLADITQQLNQSELAVLLNLLQSQTDLSIPQMAQLLNI
HSNPEMQQQLEALNQSISALTEATSQQQDSETMAPEESLKEAPSAPVILPSAEQTTLEAS
STPADMQNILAVLLSQLMKTQEPAGSLEENNSDKNSGPQGPRRTPTMPQEEAAACPPHIL
PPEKRPPEPPGPPPPPPPPPLVEGDLSSAPQELNPAVTAALLQLLSQPEAEPPGHLPHEH
QALRPMEYSTRPRPNRTYGNTDGPETGFSAIDTDERNSGPALTESLVQTLVKNRTFSGSL
SHLGESSSYQGTGSVQFPGDQDLRFARVPLALHPVVGQPFLKAEGSSNSVVHAETKLQNY
GELGPGTTGASSSGAGLHWGGPTQSSAYGKLYRGPTRVPPRGGRGRGVPY
Function
Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors.
Tissue Specificity Widely expressed.
Reactome Pathway
TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648 )

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Tourette syndrome DISX9D54 No Known Unknown [1]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Fulvestrant DM0YZC6 Approved Cyclin-dependent kinase 12 (CDK12) affects the response to substance of Fulvestrant. [17]
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11 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 12 (CDK12). [2]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Cyclin-dependent kinase 12 (CDK12). [3]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Cyclin-dependent kinase 12 (CDK12). [4]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Cyclin-dependent kinase 12 (CDK12). [5]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Cyclin-dependent kinase 12 (CDK12). [6]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide increases the expression of Cyclin-dependent kinase 12 (CDK12). [7]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Cyclin-dependent kinase 12 (CDK12). [8]
Methotrexate DM2TEOL Approved Methotrexate decreases the expression of Cyclin-dependent kinase 12 (CDK12). [9]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Cyclin-dependent kinase 12 (CDK12). [10]
DNCB DMDTVYC Phase 2 DNCB decreases the expression of Cyclin-dependent kinase 12 (CDK12). [12]
SCH 727965 DMCJLD1 Discontinued in Phase 3 SCH 727965 decreases the activity of Cyclin-dependent kinase 12 (CDK12). [16]
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⏷ Show the Full List of 11 Drug(s)
5 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Resveratrol DM3RWXL Phase 3 Resveratrol affects the phosphorylation of Cyclin-dependent kinase 12 (CDK12). [11]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Cyclin-dependent kinase 12 (CDK12). [13]
TAK-243 DM4GKV2 Phase 1 TAK-243 decreases the sumoylation of Cyclin-dependent kinase 12 (CDK12). [14]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Cyclin-dependent kinase 12 (CDK12). [15]
Coumarin DM0N8ZM Investigative Coumarin decreases the phosphorylation of Cyclin-dependent kinase 12 (CDK12). [15]
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References

1 The Ethnic-Specific Spectrum of Germline Nucleotide Variants in DNA Damage Response and Repair Genes in Hereditary Breast and Ovarian Cancer Patients of Tatar Descent. Front Oncol. 2018 Oct 2;8:421. doi: 10.3389/fonc.2018.00421. eCollection 2018.
2 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
3 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
4 Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
5 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
6 Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
7 Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
8 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
9 Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
10 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
11 Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling. J Proteome Res. 2014 Dec 5;13(12):5734-42. doi: 10.1021/pr500714a. Epub 2014 Oct 29.
12 Human relevance of an in vitro gene signature in HaCaT for skin sensitization. Toxicol In Vitro. 2015 Feb;29(1):81-4. doi: 10.1016/j.tiv.2014.08.010. Epub 2014 Sep 16.
13 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
14 Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
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 CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.
17 CRK7 modifies the MAPK pathway and influences the response to endocrine therapy. Carcinogenesis. 2009 Oct;30(10):1696-701. doi: 10.1093/carcin/bgp187. Epub 2009 Aug 3.