Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTORHZ9Y)

• DOT Name: MAP3K12-binding inhibitory protein 1 (MBIP)
• Synonyms: MAPK upstream kinase-binding inhibitory protein; MUK-binding inhibitory protein
• Gene Name: MBIP
• Related Disease:
  Hereditary progressive chorea without dementia
  Brain-lung-thyroid syndrome
  Hashimoto thyroiditis
  Thyroid gland papillary carcinoma
• UniProt ID: MBIP1_HUMAN
• Sequence:
  MAAATELNRPSSGDRNLERRCRPNLSREVLYEIFRSLHTLVGQLDLRDDVVKITIDWNKL
  QSLSAFQPALLFSALEQHILYLQPFLAKLQSPIKEENTTAVEEIGRTEMGNKNEVNDKFS
  IGDLQEEEKHKESDLRDVKKTQIHFDPEVVQIKAGKAEIDRRISAFIERKQAEINENNVR
  EFCNVIDCNQENSCARTDAIFTPYPGFKSHVKVSRVVNTYGPQTRPEGIPGSGHKPNSML
  RDCGNQAVEERLQNIEAHLRLQTGGPVPRDIYQRIKKLEDKILELEGISPEYFQSVSFSG
  KRRKVQPPQQNYSLAELDEKISALKQALLRKSREAESMATHHLP
• Function: Inhibits the MAP3K12 activity to induce the activation of the JNK/SAPK pathway. Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4.
• Tissue Specificity: Ubiquitous. High expression seen in the heart and lung.
• Reactome Pathway:
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary progressive chorea without dementia	DISW33PR	Definitive	Genetic Variation	[1]
Brain-lung-thyroid syndrome	DISSL12Z	Limited	Biomarker	[2]
Hashimoto thyroiditis	DIS77CDF	Limited	Genetic Variation	[3]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[4]

8 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 MAP3K12-binding inhibitory protein 1 (MBIP).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MAP3K12-binding inhibitory protein 1 (MBIP).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of MAP3K12-binding inhibitory protein 1 (MBIP).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of MAP3K12-binding inhibitory protein 1 (MBIP).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of MAP3K12-binding inhibitory protein 1 (MBIP).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of MAP3K12-binding inhibitory protein 1 (MBIP).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of MAP3K12-binding inhibitory protein 1 (MBIP).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of MAP3K12-binding inhibitory protein 1 (MBIP).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of MAP3K12-binding inhibitory protein 1 (MBIP).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of MAP3K12-binding inhibitory protein 1 (MBIP).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of MAP3K12-binding inhibitory protein 1 (MBIP).	[11]

References

• [1] Benign hereditary chorea and deletions outside NKX2-1: What's the role of MBIP?.Eur J Med Genet. 2018 Oct;61(10):581-584. doi: 10.1016/j.ejmg.2018.03.011. Epub 2018 Apr 3.
• [2] A further case of brain-lung-thyroid syndrome with deletion proximal to NKX2-1.Eur J Med Genet. 2017 May;60(5):257-260. doi: 10.1016/j.ejmg.2017.03.001. Epub 2017 Mar 7.
• [3] Association of Established Thyroid-stimulating Hormone and Free Thyroxine Genetic Variants with Hashimoto's Thyroiditis.Immunol Invest. 2017 Aug;46(6):625-638. doi: 10.1080/08820139.2017.1337785.
• [4] Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters.Thyroid. 2016 Sep;26(9):1276-84. doi: 10.1089/thy.2015.0665. Epub 2016 Jul 22.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.