Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEMWLZ0)

• DOT Name: THAP domain-containing protein 11 (THAP11)
• Gene Name: THAP11
• Related Disease:
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Vitamin B12 deficiency
  Methylmalonic aciduria and homocystinuria
• UniProt ID: THA11_HUMAN
• PDB ID: 2LAU; 5AJS
• Pfam ID: PF05485
• Sequence:
  MPGFTCCVPGCYNNSHRDKALHFYTFPKDAELRRLWLKNVSRAGVSGCFSTFQPTTGHRL
  CSVHFQGGRKTYTVRVPTIFPLRGVNERKVARRPAGAAAARRRQQQQQQQQQQQQQQQQQ
  QQQQQQQQQQQQSSPSASTAQTAQLQPNLVSASAAVLLTLQATVDSSQAPGSVQPAPITP
  TGEDVKPIDLTVQVEFAAAEGAAAAAAASELQAATAGLEAAECPMGPQLVVVGEEGFPDT
  GSDHSYSLSSGTTEEELLRKLNEQRDILALMEVKMKEMKGSIRHLRLTEAKLREELREKD
  RLLAMAVIRKKHGM
• Function: Transcriptional repressor that plays a central role for embryogenesis and the pluripotency of embryonic stem (ES) cells. Sequence-specific DNA-binding factor that represses gene expression in pluripotent ES cells by directly binding to key genetic loci and recruiting epigenetic modifiers.
• KEGG Pathway: Cobalamin transport and metabolism (hsa04980)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Vitamin B12 deficiency	DIS91UJ1	Strong	Biomarker	[3]
Methylmalonic aciduria and homocystinuria	DIS5921T	Limited	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of THAP domain-containing protein 11 (THAP11).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of THAP domain-containing protein 11 (THAP11).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of THAP domain-containing protein 11 (THAP11).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of THAP domain-containing protein 11 (THAP11).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of THAP domain-containing protein 11 (THAP11).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of THAP domain-containing protein 11 (THAP11).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of THAP domain-containing protein 11 (THAP11).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of THAP domain-containing protein 11 (THAP11).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of THAP domain-containing protein 11 (THAP11).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of THAP domain-containing protein 11 (THAP11).	[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 increases the methylation of THAP domain-containing protein 11 (THAP11).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of THAP domain-containing protein 11 (THAP11).	[14]

References

• [1] A transcriptional regulatory role of the THAP11-HCF-1 complex in colon cancer cell function.Mol Cell Biol. 2012 May;32(9):1654-70. doi: 10.1128/MCB.06033-11. Epub 2012 Feb 27.
• [2] THAP11, a novel binding protein of PCBP1, negatively regulates CD44 alternative splicing and cell invasion in a human hepatoma cell line.FEBS Lett. 2012 May 21;586(10):1431-8. doi: 10.1016/j.febslet.2012.04.016. Epub 2012 Apr 21.
• [3] X-Linked Cobalamin Disorder (HCFC1) Mimicking Nonketotic Hyperglycinemia With Increased Both Cerebrospinal Fluid Glycine and Methylmalonic Acid.Pediatr Neurol. 2017 Jun;71:65-69. doi: 10.1016/j.pediatrneurol.2016.12.003. Epub 2017 Jan 7.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] 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.
• [9] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] 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.
• [16] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.