Details of Drug Off-Target (DOT)

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

• DOT Name: Mediator of RNA polymerase II transcription subunit 11 (MED11)
• Synonyms: Mediator complex subunit 11
• Gene Name: MED11
• Related Disease: Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities
• UniProt ID: MED11_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 7NVR; 8GXQ; 8GXS
• Pfam ID: PF10280
• Sequence:
  MATYSLANERLRALEDIEREIGAILQNAGTVILELSKEKTNERLLDRQAAAFTASVQHVE
  AELSAQIRYLTQVATGQPHEGSSYSSRKDCQMALKRVDYARLKLSDVARTCEQMLEN
• Function: Component of the Mediator complex, a coactivator involved in the regulated 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 theee assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors.
• Reactome Pathway:
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities	DISO4YJO	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Mediator of RNA polymerase II transcription subunit 11 (MED11).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mediator of RNA polymerase II transcription subunit 11 (MED11).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mediator of RNA polymerase II transcription subunit 11 (MED11).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mediator of RNA polymerase II transcription subunit 11 (MED11).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mediator of RNA polymerase II transcription subunit 11 (MED11).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Mediator of RNA polymerase II transcription subunit 11 (MED11).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mediator of RNA polymerase II transcription subunit 11 (MED11).	[8]

References

• [1] A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. Genet Med. 2022 Oct;24(10):2194-2203. doi: 10.1016/j.gim.2022.07.013. Epub 2022 Aug 24.
• [2] 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.
• [3] 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.
• [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] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.