Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMC3CWX)

• DOT Name: Cyclin-dependent kinase 8 (CDK8)
• Synonyms: EC 2.7.11.22; EC 2.7.11.23; Cell division protein kinase 8; Mediator complex subunit CDK8; Mediator of RNA polymerase II transcription subunit CDK8; Protein kinase K35
• Gene Name: CDK8
• Related Disease:
  Autism, susceptibility to, 15
  Intellectual developmental disorder with hypotonia and behavioral abnormalities
• UniProt ID: CDK8_HUMAN
• PDB ID: 3RGF; 4CRL; 4F6S; 4F6U; 4F6W; 4F70; 4F7J; 4F7L; 4F7N; 4F7S; 4G6L; 5BNJ; 5CEI; 5FGK; 5HBE; 5HBH; 5HBJ; 5HNB; 5HVY; 5I5Z; 5ICP; 5IDN; 5IDP; 5XQX; 5XS2; 6QTG; 6QTJ; 6R3S; 6T41; 6TPA; 6Y0A
• EC Number: 2.7.11.22; 2.7.11.23
• Pfam ID: PF00069
• Sequence:
  MDYDFKVKLSSERERVEDLFEYEGCKVGRGTYGHVYKAKRKDGKDDKDYALKQIEGTGIS
  MSACREIALLRELKHPNVISLQKVFLSHADRKVWLLFDYAEHDLWHIIKFHRASKANKKP
  VQLPRGMVKSLLYQILDGIHYLHANWVLHRDLKPANILVMGEGPERGRVKIADMGFARLF
  NSPLKPLADLDPVVVTFWYRAPELLLGARHYTKAIDIWAIGCIFAELLTSEPIFHCRQED
  IKTSNPYHHDQLDRIFNVMGFPADKDWEDIKKMPEHSTLMKDFRRNTYTNCSLIKYMEKH
  KVKPDSKAFHLLQKLLTMDPIKRITSEQAMQDPYFLEDPLPTSDVFAGCQIPYPKREFLT
  EEEPDDKGDKKNQQQQQGNNHTNGTGHPGNQDSSHTQGPPLKKVRVVPPTTTSGGLIMTS
  DYQRSNPHAAYPNPGPSTSQPQSSMGYSATSQQPPQYSHQTHRY
• Function: Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.
• Reactome Pathway:
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Generic Transcription Pathway (R-HSA-212436)
  SMAD2/SMAD3 (R-HSA-2173796)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism, susceptibility to, 15	DISYCG6A	Definitive	Autosomal dominant	[1]
Intellectual developmental disorder with hypotonia and behavioral abnormalities	DISRNN72	Strong	Autosomal dominant	[1]

14 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 8 (CDK8).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cyclin-dependent kinase 8 (CDK8).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyclin-dependent kinase 8 (CDK8).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cyclin-dependent kinase 8 (CDK8).	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cyclin-dependent kinase 8 (CDK8).	[6]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Cyclin-dependent kinase 8 (CDK8).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cyclin-dependent kinase 8 (CDK8).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Cyclin-dependent kinase 8 (CDK8).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Cyclin-dependent kinase 8 (CDK8).	[3]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cyclin-dependent kinase 8 (CDK8).	[10]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Cyclin-dependent kinase 8 (CDK8).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cyclin-dependent kinase 8 (CDK8).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cyclin-dependent kinase 8 (CDK8).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cyclin-dependent kinase 8 (CDK8).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cyclin-dependent kinase 8 (CDK8).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cyclin-dependent kinase 8 (CDK8).	[14]

References

• [1] De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. Am J Hum Genet. 2019 Apr 4;104(4):709-720. doi: 10.1016/j.ajhg.2019.02.006. Epub 2019 Mar 21.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] 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.
• [5] Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin Diagn Lab Immunol. 2004 Jan;11(1):63-9. doi: 10.1128/cdli.11.1.63-69.2004.
• [6] Elucidating progesterone effects in breast cancer: cross talk with PDGF signaling pathway in smooth muscle cell. J Cell Biochem. 2007 Jan 1;100(1):174-83. doi: 10.1002/jcb.21045.
• [7] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. 2008 Oct;29(10):2001-10.
• [10] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
• [11] The HSP90 inhibitor 17-AAG synergizes with doxorubicin and U0126 in anaplastic large cell lymphoma irrespective of ALK expression. Exp Hematol. 2006 Dec;34(12):1670-9. doi: 10.1016/j.exphem.2006.07.002.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.